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Cell Growth & Differentiation Vol. 12, 363-369, July 2001
© 2001 American Association for Cancer Research

Phosphatidylinositol 3-Kinase Signaling Controls Levels of Hypoxia-inducible Factor 11

Bing-Hua Jiang2, Guoqiang Jiang3, Jenny Z. Zheng, Zhimin Lu4, Tony Hunter5 and Peter K. Vogt6

Department of Molecular and Experimental Medicine, BCC239, The Scripps Research Institute [B-H. J., J. Z. Z., P. K. V.], and Molecular Biology and Virology Laboratory, The Salk Institute for Biological Studies [G. J., Z. L., T. H.], La Jolla, California 92037


    Abstract
 TOP
 Abstract
 Introduction
 Results
 Discussion
 Materials and Methods
 References
 
The phosphatidylinositol 3-kinase (PI3K) signaling pathway has inherent oncogenic potential. It is up-regulated in diverse human cancers by either a gain of function in PI3K itself or in its downstream target Akt or by a loss of function in the negative regulator PTEN. However, the complete consequences of this up-regulation are not known. Here we show that insulin and epidermal growth factor or an inactivating mutation in the tumor suppressor PTEN specifically increase the protein levels of hypoxia-inducible factor (HIF) 1{alpha} but not of HIF-1ß in human cancer cell lines. This specific elevation of HIF-1{alpha} protein expression requires PI3K signaling. In the prostate carcinoma-derived cell lines PC-3 and DU145, insulin- and epidermal growth factor-induced expression of HIF-1{alpha} was inhibited by the PI3K-specific inhibitors LY294002 and wortmannin in a dose-dependent manner. HIF-1ß expression was not affected by these inhibitors. Introduction of wild-type PTEN into the PTEN-negative PC-3 cell line specifically inhibited the expression of HIF-1{alpha} but not that of HIF-1ß. In contrast to the HIF-1{alpha} protein, the level of HIF-1{alpha} mRNA was not significantly affected by PI3K signaling. Vascular endothelial growth factor reporter gene activity was induced by insulin in PC-3 cells and was inhibited by the PI3K inhibitor LY294002 and by the coexpression of a HIF-1 dominant negative construct. Vascular endothelial growth factor reporter gene activity was also inhibited by expression of a dominant negative PI3K construct and by the tumor suppressor PTEN.


    Introduction
 TOP
 Abstract
 Introduction
 Results
 Discussion
 Materials and Methods
 References
 
Oncogenic transformation is characterized by gain of function in growth-promoting oncoproteins and loss of function in growth-attenuating tumor suppressor proteins. Both types of aberrant regulation are seen in the signaling pathway mediated by PI3K7 (1, 2, 3, 4) . PI3K phosphorylates inositol lipids at the D-3 position, producing phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. It is linked via its regulatory subunit p85 to upstream receptors that are activated by growth factors or insulin. A downstream target of PI3K is the serine-threonine kinase Akt that is activated by phosphatidylinositol-dependent kinase 1 (5, 6, 7, 8) . In human cancers, the PI3K pathway is up-regulated by several different mechanisms. The gene coding for the catalytic subunit of PI3K is amplified in cervical and ovarian carcinomas (9, 10, 11) . The genes of the PI3K targets AKT1 and AKT2 are amplified and overexpressed in breast, gastric, and ovarian cancers (12, 13, 14, 15) . The tumor suppressor PTEN, an antagonist of PI3K, is frequently lost in glioblastoma, endometrial cancer, carcinoma of the prostate, and melanoma (3 , 16, 17, 18, 19, 20) . In experimental systems, constitutively active PI3K or Akt is oncogenic in vitro and in vivo. A mutated version of the of the PI3K catalytic subunit functions as the tumorigenic determinant in the avian retroviruses ASV16 and ASV8905 (1 , 2) . These viruses transform chicken embryo fibroblasts in culture and induce hemangiosarcomas in young chickens. Myristylated Akt constitutively expressed from a retroviral vector has the same cell-transforming and tumor-inducing effect as does PI3K. A murine retrovirus carrying Akt induces lymphomas (21) . PI3K also plays an essential role in the formation of the vascular system during embryonal development, and overexpression of PI3K or Akt is highly angiogenic (4) .

Although a role of PI3K signaling in cancer and in angiogenesis is firmly established, important downstream effectors of these events still need to be identified, characterized, and integrated in the pathway. One of these downstream effectors is HIF-1, a protein of increasing importance in human disease (22) . HIF-1 is a heterodimeric transcriptional activator composed of HIF-1{alpha} and HIF-1ß subunits (23 , 24) . It regulates the expression of many genes including VEGF, heme oxygenase 1, inducible nitric oxide synthase, aldolase, enolase, and lactate dehydrogenase A (25) . Levels of HIF-1 activity are correlated with tumorigenicity and angiogenesis in nude mice (26 , 27) . HIF-1 is overexpressed in many human cancers (28) . Inactivation of HIF-1 is associated with defects in embryonic vascularization (29 , 30) . In PTEN-negative PC-3 cells, HIF-1{alpha} expression is induced by EGF and inhibited by PI3K inhibitors (31) . Here we show that activation of PI3K signaling by insulin or by loss of PTEN induces elevated levels of HIF-1{alpha} but not HIF-1ß protein. Inhibition of PI3K activity by LY294002 or wortmannin or wild-type PTEN reduces the levels of HIF-1{alpha} but not the levels of HIF-1ß. However, PI3K signaling does not significantly alter the steady-state levels of HIF-1{alpha} mRNA, suggesting that it affects expression of HIF-1{alpha} posttranscriptionally. While this work was in progress, three reports appeared that also showed regulation of HIF-1{alpha} by the PI3K/PTEN/Akt/mTor pathway (31, 32, 33) . Our studies confirm and expand the results of these earlier investigations.


    Results
 TOP
 Abstract
 Introduction
 Results
 Discussion
 Materials and Methods
 References
 
Insulin or Loss of Function of PTEN Increases Levels of HIF-1{alpha} in Cancer Cell Lines.
Insulin induces the expression of VEGF through the PI3K pathway (4) . Because HIF-1 is a transcriptional regulator of VEGF expression, we asked whether insulin induces HIF-1. Four human cancer cell lines were used in this study: the osteosarcoma-derived cell line U2-OS; renal carcinoma cell line ACHN; and prostate cancer cell lines DU145 and PC-3. U2-OS, ACHN, and DU145 contain wild-type PTEN; PC-3 lacks active PTEN protein (34) . The cells were cultured in MEM with serum for 24 h and then exposed to 200 µM insulin for 6 h (Fig. 1)Citation . Insulin induced high levels of HIF-1{alpha} expression in ACHN, DU145, and PC-3 cells and a lower level of HIF-1{alpha} expression in U2-OS cells. In contrast, insulin treatment had no effect on the levels of HIF-1ß. The apparent reduction of HIF-1ß levels in U2-OS and ACHN cells seen in Fig. 1Citation proved to be insignificant, and the reduction was not observed consistently in replicate experiments. Serum-starved PC-3 cells, which lack PTEN, contained high levels of HIF-1{alpha} and HIF-1ß, and insulin elevated the levels of HIF-1{alpha} but not the levels of HIF-1ß further. PC-3 cells also contained constitutively high levels of Akt kinase activity (data not shown). These results document induction of HIF-1{alpha} by insulin. Basal levels of HIF-1 are low in PTEN wild-type cells and high in the PTEN-defective cell line.



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Fig. 1. Expression of HIF-1{alpha} is increased by the addition of insulin or with the mutation of PTEN in cancer cell lines. U2-OS, ACHN, DU145, AND PC-3 cells were cultured in serum-free MEM with Earle’s salts for 24 h, followed by incubation in the absence or presence of 200 nM insulin for 6 h. Nuclear extracts were prepared, and 10 µg of the nuclear extracts were used for immunoblot analysis and detected by antibodies against HIF-1{alpha} and HIF-1ß.

 
PI3K Signaling Mediates the Induction of HIF-1{alpha}.
Insulin activates PI3K, which in turn induces the expression of VEGF (4) . To test whether the up-regulation of HIF-1{alpha} by insulin is also dependent on PI3K, we studied the effect of two inhibitors of PI3K, LY294002 and wortmannin, in PC-3 and DU145 cells. Both inhibitors prevented the induction of HIF-1{alpha} by insulin and at higher concentrations reduced HIF-1{alpha} levels below basal values (Fig. 2)Citation . HIF-1{alpha} expression in PC-3 cells appeared more sensitive to the inhibitors than that in DU145 cells. The absence of PTEN in PC-3 cells may not only increase Akt activity but may also make this activity more susceptible to the upstream inhibitor. There was no effect of the inhibitors on the expression of HIF-1ß. These data suggest that PI3K mediates HIF-1 expression in a subunit-specific manner, discriminating between HIF-1{alpha} and HIF-1ß. For comparison, the effect of EGF on the expression of HIF-1 was tested in PC-3 cells that express HIF-1 constitutively. EGF had a marginal effect on the levels of HIF-1{alpha}, and LY294002 and wortmannin strongly inhibited HIF-1{alpha} expression in the presence of EGF (Fig. 3)Citation . In DU145 cells that have low levels of HIF-1{alpha}, EGF caused a substantial up-regulation, and the PI3K inhibitors reduced EGF-induced HIF-1{alpha} expression significantly. Total cell extracts gave similar results for HIF-1{alpha} expression (data not shown), indicating that regulation occurred at the level of protein expression and not by differential subcellular localization. In these cells, EGF did not affect the levels of HIF-1ß.



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Fig. 2. PI3K signaling mediates specific expression of HIF-1{alpha} induced by insulin. PC-3 (A) and DU145 (B) cells were cultured without serum for 24 h. The PI3K-specific inhibitors LY294002 and wortmannin at the indicated concentrations were added 30 min before the addition of insulin. The cells were incubated in the presence (+) or absence (-) of insulin for 6 h. Nuclear extracts were prepared and used to analyze HIF-1{alpha} and HIF-1ß protein expression. The exposure times for immunoblots A and B were different, and the signals on these two blots are not comparable.

 


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Fig. 3. PI3K signaling mediates specific expression of HIF-1{alpha} induced by EGF. PC-3 (A) and DU145 (B) cells were cultured in serum-free medium for 24 h. The PI3K inhibitors LY294002 and wortmannin were added at the indicated concentration 30 min before the addition of 20 ng/ml EGF. The cells were incubated in the presence (+) or absence (-) of EGF for 6 h. HIF-1{alpha} and HIF-1ß protein expression was analyzed as described above. The exposure times for immunoblots A and B were different, and the signals on these two blots are not comparable.

 
The Effect of PI3K Signaling on HIF-1{alpha} mRNA Levels.
To test whether activation of PI3K increased the steady-state levels of HIF-1{alpha} mRNA, total RNA was isolated from serum-starved PC-3 and DU145 cells that had been treated with 200 µM insulin or 20 ng/ml EGF in the absence or presence of the PI3K inhibitor LY294002. The RNA was analyzed by Northern blotting (Fig. 4)Citation . In contrast to the levels of HIF-1{alpha} protein, the levels of HIF-1{alpha} mRNA in DU145 cells were not induced by EGF or insulin and were not reduced by the PI3K inhibitor LY294002 (Fig. 4B)Citation . In the PTEN-negative PC-3 cells, HIF-1{alpha} mRNA was modestly induced by EGF and insulin, and this induction was inhibited by the PI3K inhibitor LY294002 (Fig. 4A)Citation . However, the reduction of HIF-1{alpha} mRNA levels by LY294002 was minor when compared with the changes of HIF-1{alpha} protein levels. In PC-3 cells, expression of the HIF-1{alpha} protein was extinguished by 10 µM LY294002 (Figs. 2Citation and 3Citation ). The difference in response of HIF-1{alpha} mRNA to PI3K signaling in DU145 and PC-3 cells is probably due to the status of PTEN in these cells. DU145 cells contain normal PTEN that attenuates PI3K and Akt activity. PC-3 cells lack PTEN, resulting in constitutive activation of Akt. These observations suggest that (a) in DU145 cells, the levels of HIF-1{alpha} mRNA are not affected by PI3K signaling; (b) in PC-3 cells, HIF-1{alpha} mRNA levels are slightly affected by PI3K activity; and (c) insulin and EGF increase levels of HIF-1{alpha} protein expression mainly at the posttranscriptional level.



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Fig. 4. The effect of PI3K activity on HIF-1{alpha} mRNA levels. PC-3 and DU145 cells were cultured in serum-free medium for 24 h. The PI3K inhibitor LY294002 was added at the indicated concentration 30 min before the addition of insulin and EGF, followed by incubation in the absence (-) or presence (+) of 200 nM insulin or 20 ng/ml EGF as indicated for 6 h. Total RNA was isolated, and 10-µg aliquots were separated by electrophoresis in 2.2 M formaldehyde/1.1% agarose gels and transferred to a nylon membrane. The membrane was probed by using a 32P-labeled HIF-1{alpha} cDNA fragment.

 
PTEN Inhibits the Expression of HIF-1{alpha}.
The tumor suppressor PTEN is an antagonist of PI3K signaling and functions by removing the phosphate at the three positions of phosphatidylinositol bisphosphate and phosphatidylinositol trisphosphate. In PTEN-deficient PC-3 cells, levels of HIF-1{alpha} are constitutively high (Fig. 1)Citation . To test the role of PTEN in the regulation of HIF-1{alpha}, wild-type PTEN expression was restored in PC-3 cells by expression from the pCR2 retroviral vector. The result was a strong reduction of HIF-1{alpha} protein levels (Fig. 5)Citation . HIF-1ß expression was not affected by PTEN. These observations further support the conclusion that PI3K signals are essential for the regulation of HIF-1{alpha} but not HIF-1ß and that interference with PI3K signals by chemical inhibitors or by a cellular antagonist leads to a reduction of HIF-1{alpha} levels.



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Fig. 5. In PC-3 cells, PTEN inhibits HIF-1{alpha} but not HIF-1ß protein expression. PC-3 cells were infected three times with the retroviral expression vector pCR2 alone or carrying the wild-type PTEN insert as described. After infection, the cells were cultured in growth medium for 48 h and then switched to serum-free MEM with Earle’s salts for 24 h, followed by incubation in the presence or absence of 200 nM insulin for 6 h. HIF-1{alpha} and HIF-1ß protein expression was determined by immunoblot analysis.

 
HIF-1 Is Required for the Transcriptional Activation of VEGF by PI3K.
It was shown previously that in avian cells, PI3K signaling leads to an up-regulation of VEGF (4) . This observation was confirmed for PC-3 cells. A reporter construct containing a 2.5-kb fragment of the 5'-flanking region from the human VEGF gene in the pGL2 vector was transfected into PC-3 cells. After overnight incubation in serum-containing medium, the cells were switched to serum-free medium with or without insulin. Insulin induced the activity of the reporter, and this induction was inhibited by LY294002 (Fig. 6A)Citation . Cotransfection of PTEN or of a dominant negative construct of PI3K, p85{Delta}iSH2N (35) , also inhibited reporter activity in three cell lines (PC-3, U373, and P19; Fig. 6BCitation ). These results suggest that PI3K activity is an important component in the control of VEGF transcription. A possible role for HIF-1 in the regulation of VEGF was explored with a dominant negative HIF-1{alpha} construct, HIF-1{alpha}{Delta}NB{Delta}AB (23 , 36) , cotransfected with the VEGF reporter plasmid. This construct inhibited insulin-induced VEGF reporter activity in PC-3 cells in a dose-dependent manner (Fig. 6C)Citation , suggesting a requirement for HIF-1 in the transcriptional up-regulation of VEGF by PI3K. A recent study shows that a reporter containing the promoter sequence of human enolase gene ENO1 was similarly activated by PI3K via HIF-1{alpha} (31) .



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Fig. 6. VEGF reporter activity is mediated by the expression of HIF-1 and PI3K signaling. A, the VEGF reporter was cotransfected with pCMVßGal plasmids into PC-3 cells and incubated with MEM supplemented with 10% fetal bovine serum overnight. The cells were switched to serum-free medium in the presence or absence of 20 µM LY294002 and 200 nM insulin for 36 h. Relative Luc activity was determined by the ratio of Luc:ß-Gal activity and normalized to the value in the solvent DMSO control. B, VEGF reporter and pCMVßGal plasmids were cotransfected with vector or 0.6 or 1.2 µg of HIF-1{alpha}{Delta}NB{Delta}AB plasmid, respectively, into PC-3 cells. After transfection, the cells were cultured and treated as indicated in A. C, VEGF reporter and pCMVßGal plasmids were cotransfected with pSG5 vector or vector carrying the PI3K dominant negative construct, p85{Delta}iSH2N, or tumor suppressor PTEN. The PC-3 cells were maintained in growth medium after transfection. The relative Luc activity was determined 48 h after transfection as described above.

 

    Discussion
 TOP
 Abstract
 Introduction
 Results
 Discussion
 Materials and Methods
 References
 
We have reported previously that the PI3K/Akt signaling pathway mediates angiogenesis and expression of VEGF in endothelial cells (4) . In the current study, we show that activation of PI3K leads to increased levels of HIF-1{alpha} protein (Figs. 1Citation 2Citation 3)Citation and positively regulates HIF-1{alpha}-mediated transcription of VEGF in diverse tumor cell lines (Fig. 6)Citation . These observations suggest that PI3K and (by implication) its downstream target Akt affect angiogenesis by controlling the levels of HIF-1{alpha}.

Several lines of evidence support the conclusion that PI3K signals elevate levels of HIF-1{alpha} protein in the cells. First, treatment with insulin or EGF results in higher levels of HIF-1{alpha} in several human cancer cell lines (Fig. 1)Citation . Signals from insulin or EGF are processed by PI3K and hence place PI3K in control of HIF-1{alpha}. Second, the insulin- or EGF-induced increase in HIF-1{alpha} can be largely or completely abolished by the PI3K inhibitors LY294002 or wortmannin as well as by overexpression of PTEN (Figs. 2Citation , 3Citation , and 5Citation ). These results demonstrate a requirement for PI3K in the increase of HIF-1{alpha}. Third, insulin or EGF induces higher levels of HIF-1{alpha}, but not of HIF-1ß (Figs. 1Citation 2Citation 3)Citation . The effect of the EGF- or insulin-initiated signal is therefore clearly HIF-1-subunit specific. Similar results have been presented in a recent study showing that EGF induces HIF-1{alpha} and that LY29A002 inhibits this induction (31) .

Activation of PI3K leads to increased HIF-1{alpha} protein levels but not to a corresponding increase in the steady-state levels of HIF-1{alpha} mRNA (Fig. 4)Citation . Therefore, PI3K regulates HIF-1{alpha} mainly by altering either the stability of the HIF-1{alpha} protein or the efficiency of HIF-1{alpha} mRNA translation. Existing data favor the former alternative. A recent report (32) provides strong evidence that Akt stabilizes HIF-1{alpha}, consistent with results of the current study. The stability of the HIF-1{alpha} protein is regulated by the proteasomal degradation pathway (37, 38, 39, 40, 41) . HIF-1{alpha} interacts with the tumor suppressors p53 and VHL protein (pVHL). The latter is a subunit of an E3 ubiquitin ligase. The pVHL interaction is particularly significant for the regulation of HIF-1{alpha} levels because pVHL directs the oxygen-dependent ubiquitination of HIF-1{alpha} (42, 43, 44, 45) . Stabilization of HIF-1{alpha} may reflect a failure of pVHL-mediated ubiquitination. Because proteasomal degradation is often positively regulated by phosphorylation, one might speculate that PI3K/Akt could inhibit a protein kinase or activate a phosphatase and thereby interfere with the interaction between HIF-1{alpha} and pVHL. This proposal on the effect of PI3K signaling on pVHL function can be tested experimentally. The control of HIF-1{alpha} levels appears to be an important aspect of pVHL function. All pVHL mutants linked to the VHL syndrome fail to regulate HIF-1{alpha} (38) . Tumors in VHL patients are highly vascularized, possibly as a result of the overexpression of HIF-1{alpha}-regulated genes, e.g., VEGF.

In avian cells, PI3K signaling leads to an up-regulation of VEGF, an important determinant in angiogenesis (4) . HIF-1{alpha} regulates VEGF transcription by binding to the VEGF promoter (46) . The current study shows that HIF-1{alpha} induces VEGF expression on stimulation by insulin. This induction is sensitive to inhibitors of PI3K, to expression of a dominant negative p85 subunit of PI3K, and to overexpression of PTEN (Fig. 6)Citation . These results identify HIF-1{alpha} as a critical component in PI3K/Akt-mediated angiogenesis and suggest that changes in the level of the HIF-1{alpha} protein will be significant for angiogenesis and consequently for tumor growth.

The data reported here raise interesting questions concerning the determinants of signal specificity. PI3K occupies a central position in signaling, accepting input from diverse upstream sources, e.g., insulin or EGF, and affecting a host of downstream activities. PI3K/Akt may be part of a general mechanism that controls angiogenesis and tumorigenesis through pVHL/HIF-1{alpha}/VEGF and is sensitive to modulation by many different factors. Abnormal regulation of PI3K/Akt is represented by the overexpression or amplification of the corresponding gene or loss of the negative regulator PTEN and is present in many human tumors including glioblastoma, endometrial carcinoma, prostate carcinoma, and melanoma (16 , 17 , 47) . This signaling cascade is therefore of importance for both mechanistic understanding and therapeutic intervention.

HIF-1{alpha} heterodimerizes only with HIF-1ß, and HIF-1{alpha} is the limiting component of that pair (48) . In contrast, HIF-1ß also forms heterodimers with other transcription factors (e.g., the aryl hydrocarbon receptor) to achieve distinct cellular functions (49) . The HIF-1ß/aryl hydrocarbon receptor heterodimer acts as a receptor for dioxin (50 , 51) . Our current observation that PI3K increases the levels of HIF-1{alpha} but not of HIF-1ß points to an important aspect of signal specificity in the PI3K cascade allowing an increase in HIF-1{alpha}/HIF-1ß heterodimers but not in heterodimers of HIF-ß with other transcription factors. This suggests that chemotherapeutic agents could selectively target HIF-1{alpha}.

In summary, we demonstrated that the levels of HIF-1{alpha} are controlled by PI3K and may represent a critical component in PI3K/Akt-dependent angiogenesis and tumorigenesis. HIF-1{alpha} and its regulatory signals emerge as potential targets for therapeutic intervention in cancer.


    Materials and Methods
 TOP
 Abstract
 Introduction
 Results
 Discussion
 Materials and Methods
 References
 
Cell Culture.
U2-OS and ACHN are human osteosarcoma and renal carcinoma-derived cell lines, respectively. DU145 and PC-3 are metastatic prostate carcinoma-derived cell lines. U373 is a human glioblastoma cell line, and P19 is a mouse teratocarcinoma cell line. PC-3 cells were maintained in Kaighn’s modification of F-12 medium (Life Technologies, Inc., Grand Island, NY) supplemented with 10% fetal bovine serum (Intergen, Purchase, NY). ACHN, U2-OS, DU145, and P19 cells were maintained in MEM with Earle’s salts and 10% fetal bovine serum. U373 cells were maintained in MEM with 10% fetal bovine serum and MEM vitamins (Sigma Chemical Co., St. Louis, MO). For insulin and EGF treatment, the cells were switched to serum-free MEM for 24 h and then incubated with 200 nM insulin or 20 ng/ml EGF in the presence or absence of the PI3K inhibitors LY294002 or wortmannin for 6 h.

DNA Constructs.
The dominant negative form of PI3K, p85{Delta}iSH2N, and wild type PTEN were subcloned into mammalian expression vector pSG5 (Stratagene, La Jolla, CA) and the retroviral expression vector pCR2 (36) , respectively. The dominant negative form of HIF-1, HIF-1{alpha}{Delta}NB{Delta}AB, was subcloned into pCEP4 as described previously (23) . A 2.65-kb KpnI-BssHII fragment of the human VEGF gene promoter was inserted into the pGL2 basic vector (Promega, Madison, WI) as described previously (46) .

Retroviral Packaging and Infections.
The HEK293-T human epithelial kidney cell line was cultured in DMEM supplemented with 10% fetal bovine serum at 37°C. For retrovirus production, HEK293-T cells were transiently transfected by calcium phosphate precipitation with 10 µg of amphotropic packaging vector pCL.ECO (36) and 15 µg of recombinant retrovirus vector or vector carrying the wild-type PTEN construct as described previously (36) . Media containing progeny virus were harvested at 36, 48, and 60 h after transfection, pooled, and stored at -70°C. PC-3 cells were seeded at 6 x 105 cells/60-mm dish, and after 24 h, the cells were infected three times at 12-h intervals with virus stock containing 5 µg/ml Polybrene (36) .

Preparation of Nuclear Extracts and Immunoblot Analysis.
Cell pellets were washed once with ice-cold PBS and once with buffer A [10 mM Tris-HCl (pH 7.6), 1.5 mM MgCl2, and 10 mM KCl] and collected by centrifugation at 2,000 x g at 4°C for 5 min. The cell pellets were resuspended in 5 packed cell volumes of buffer A supplemented with 2 mM DTT, 0.4 mM phenylmethylsulfonyl fluoride, 1 mg/ml leupeptin, 1 mg/ml aprotinin, 1 mg/ml pepstatin, and 0.5 M sodium vanadate. After a 5-min incubation on ice, cells were lysed by 30 strokes in a glass Dounce homogenizer with a type B pestle. Nuclei were pelleted by centrifugation at 14,000 x g at 4°C for 10 min and resuspended in 3.5 packed nuclear volumes of buffer C [0.42 M KCl, 20 mM Tris-HCl (pH 7.6), 20% glycerol, and 1.5 mM MgCl2] supplemented with 2 mM DTT, 0.4 mM phenylmethylsulfonyl fluoride, 1 mg/ml leupeptin, 1 mg/ml aprotinin, 1 mg/ml pepstatin, and 0.5 mM sodium vanadate as described previously (23) . Nuclear proteins were extracted by mixing at 4°C for 30 min and clarified by centrifugation at 15,000 x g for 15 min. Aliquots (10 µg) of nuclear extracts were resolved in SDS-polyacrylamide gels and transferred to nitrocellulose membranes. Protein bands were detected by immunoblot analysis as described previously (35) with antibodies specific for HIF-1{alpha} (Transduction Laboratories, Lexington, KY) and HIF-1ß (48) .

Preparation of RNA and Northern Blots.
PC-3 and DU145 cells were cultured and treated with insulin or EGF as described above. Total RNA was isolated using RNA STAT-60 (Tel-Test Inc., Friendswood, TX), and aliquots of 10 µg of total RNA were separated by electrophoresis in 2.2 M formaldehyde/1.1% agarose gel and transferred to a nylon membrane (Schleicher & Schuell, Keene, NH). The membrane was probed with a 32P-labeled HIF-1{alpha} cDNA fragment.

Transient Transfection and Luc Assays.
PC-3, U373, and P19 cells were maintained in culture as described above. Plasmids were prepared by using a Qiagen plasmid midi kit (Qiagen, Valencia, CA) and transfected into cells using LipofectAMINE (Life Technologies, Inc., Gaithersburg, MD). After transfection, cells were given fresh medium. For insulin treatment, cells were grown overnight in fresh medium and then switched to serum-free medium in the presence or absence of insulin and the PI3K inhibitor LY294002 for 36 h. Cells transfected with the dominant negative PI3K construct or with the tumor suppressor PTEN were cultured in fresh medium for 48 h before harvest. The cells were lysed using passive lysis buffer (Promega). Protein concentrations were determined using a Bio-Rad protein assay reagent (Bio-Rad, Hercules, CA). Luc activity was measured with a luminometer using Luc assay systems (Promega). Light production was measured for 15 s, and the values were corrected by subtracting the readings obtained with nontransfected cells. The ß-Gal activity was assayed in 100 mM sodium phosphate buffer (pH 7.5) by the hydrolysis of 0-nitrophenyl-ß-D-galactopyranoside at 37°C for 1 h and measured by the absorbance at 420 nm against a mock-transfected control. The ratio of Luc:ß-Gal activity was calculated as relative Luc activity for each sample.


    Acknowledgments
 
We thank W. K. Cavenee, C. Joazeiro, and J. A. Forsythe for providing PTEN, the pCR2 retroviral vector, and human VEGF reporter plasmids, respectively. Anke Waha’s help with manuscript preparation is gratefully acknowledged.


    Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by USPHS Grants CA 42564 and 78230 (to P. K. V.) and CA14195, and CA82863 (to T. H.) and the Sam and Rose Stein Endowment Fund. This is manuscript number 13942-MEM at The Scripps Research Institute. Back

2 Recipient of a fellowship from the National Cancer Institute. Present address: Mary Babb Randolph Cancer Center and Department of Microbiology and Immunology, West Virginia University, Morgantown, WV 26506. Back

3 Recipient of a fellowship from the American Cancer Society. Present address: Molecular Endocrinology and Metabolic Disorders, Merck & Co., Inc., Rahway, NJ 07065. Back

4 Recipient of a Pioneer Fund Fellowship. Back

5 A Frank and Else Schilling American Cancer Society Research Professor. Back

6 To whom requests for reprints should be addressed, at Department of Molecular and Experimental Medicine, BCC239, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 784-9728; Fax: (858) 784-2070; E-mail: pkvogt{at}scripps.edu Back

7 The abbreviations used are: PI3K, phosphatidylinositol 3-kinase; HIF, hypoxia-inducible factor; EGF, epidermal growth factor; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau; Luc, luciferase; ß-Gal, ß-galactosidase. Back

Received for publication 3/ 1/01. Revision received 5/18/01. Accepted for publication 5/22/01.


    References
 TOP
 Abstract
 Introduction
 Results
 Discussion
 Materials and Methods
 References
 

  1. Chang H. W., Aoki M., Fruman D., Auger K. R., Bellacosa A., Tsichlis P. N., Cantley L. C., Roberts T. M., Vogt P. K. Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. Science (Wash. DC), 276: 1848-1850, 1997.[Abstract/Free Full Text]
  2. Aoki M., Schetter C., Himly M., Batista O., Chang H. W., Vogt P. K. The catalytic subunit of phosphoinositide 3-kinase: requirements for oncogenicity. J. Biol. Chem., 275: 6267-6275, 2000.[Abstract/Free Full Text]
  3. Cantley L. C., Neel B. G. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc. Natl. Acad. Sci. USA, 96: 4240-4245, 1999.[Abstract/Free Full Text]
  4. Jiang B. H., Zheng J. Z., Aoki M., Vogt P. K. Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc. Natl. Acad. Sci. USA, 97: 1749-1753, 2000.[Abstract/Free Full Text]
  5. Chan T. O., Rittenhouse S. E., Tsichlis P. N. AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu. Rev. Biochem., 68: 965-1014, 1999.[Medline]
  6. Datta S. R., Brunet A., Greenberg M. E. Cellular survival: a play in three Akts. Genes Dev., 13: 2905-2927, 1999.[Free Full Text]
  7. Toker A., Newton A. C. Cellular signaling: pivoting around PDK-1. Cell, 103: 185-188, 2000.[Medline]
  8. Vanhaesebroeck B., Alessi D. R. The PI3K-PDK1 connection: more than just a road to PKB. Biochem. J., 346 (Part 3): 561-576, 2000.
  9. Andrew S. PIK3CA: determining its role in cellular proliferation and ovarian cancer. Clin. Genet., 56: 190-191, 1999.[Medline]
  10. Ma Y. Y., Wei S. J., Lin Y. C., Lung J. C., Chang T. C., Whang-Peng J., Liu J. M., Yang D. M., Yang W. K., Shen C. Y. PIK3CA as an oncogene in cervical cancer. Oncogene, 19: 2739-2744, 2000.[Medline]
  11. Shayesteh L., Lu Y., Kuo W. L., Baldocchi R., Godfrey T., Collins C., Pinkel D., Powell B., Mills G. B., Gray J. W. PIK3CA is implicated as an oncogene in ovarian cancer. Nat. Genet., 21: 99-102, 1999.[Medline]
  12. Bellacosa A., de Feo D., Godwin A. K., Bell D. W., Cheng J. Q., Altomare D. A., Wan M., Dubeau L., Scambia G., Masciullo V. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int. J. Cancer, 64: 280-285, 1995.[Medline]
  13. Staal S. P. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc. Natl. Acad. Sci. USA, 84: 5034-5037, 1987.[Abstract/Free Full Text]
  14. Thompson F. H., Nelson M. A., Trent J. M., Guan X. Y., Liu Y., Yang J. M., Emerson J., Adair L., Wymer J., Balfour C., Massey K., Weinstein R., Alberts D. S., Taetle R. Amplification of 19q13.1-q13.2 sequences in ovarian cancer. G-band, FISH, and molecular studies. Cancer Genet. Cytogenet., 87: 55-62, 1996.[Medline]
  15. Yuan Z. Q., Sun M., Feldman R. I., Wang G., Ma X., Jiang C., Coppola D., Nicosia S. V., Cheng J. Q. Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer. Oncogene, 19: 2324-2330, 2000.[Medline]
  16. Besson A., Robbins S. M., Yong V. W. PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis. Eur. J. Biochem., 263: 605-611, 1999.[Medline]
  17. Di Cristofano A., Pandolfi P. P. The multiple roles of PTEN in tumor suppression. Cell, 100: 387-390, 2000.[Medline]
  18. Esteller M., Xercavins J., Reventos J. Advances in the molecular genetics of endometrial cancer. Oncol. Rep., 6: 1377-1382, 1999.[Medline]
  19. Ittmann M. M. Chromosome 10 alterations in prostate adenocarcinoma. Oncol. Rep., 5: 1329-1335, 1998.[Medline]
  20. Rasheed B. K., Wiltshire R. N., Bigner S. H., Bigner D. D. Molecular pathogenesis of malignant gliomas. Curr. Opin. Oncol., 11: 162-167, 1999.[Medline]
  21. Staal S. P., Hartley J. W. Thymic lymphoma induction by the AKT8 murine retrovirus. J. Exp. Med., 167: 1259-1264, 1988.[Abstract/Free Full Text]
  22. Semenza G. L. HIF-1 and human disease: one highly involved factor. Genes Dev., 14: 1983-1991, 2000.[Free Full Text]
  23. Jiang B. H., Rue E., Wang G. L., Roe R., Semenza G. L. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J. Biol. Chem., 271: 17771-17778, 1996.[Abstract/Free Full Text]
  24. Wang G. L., Jiang B. H., Rue E. A., Semenza G. L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA, 92: 5510-5514, 1995.[Abstract/Free Full Text]
  25. Semenza G. L. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit. Rev. Biochem. Mol. Biol., 35: 71-103, 2000.[Medline]
  26. Jiang B. H., Agani F., Passaniti A., Semenza G. L. V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res., 57: 5328-5335, 1997.[Abstract/Free Full Text]
  27. Maxwell P. H., Dachs G. U., Gleadle J. M., Nicholls L. G., Harris A. L., Stratford I. J., Hankinson O., Pugh C. W., Ratcliffe P. J. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc. Natl. Acad. Sci. USA, 94: 8104-8109, 1997.[Abstract/Free Full Text]
  28. Zhong H., De Marzo A. M., Laughner E., Lim M., Hilton D. A., Zagzag D., Buechler P., Isaacs W. B., Semenza G. L., Simons J. W. Overexpression of hypoxia-inducible factor 1{alpha} in common human cancers and their metastases. Cancer Res., 59: 5830-5835, 1999.[Abstract/Free Full Text]
  29. Iyer N. V., Kotch L. E., Agani F., Leung S. W., Laughner E., Wenger R. H., Gassmann M., Gearhart J. D., Lawler A. M., Yu A. Y., Semenza G. L. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 {alpha}. Genes Dev., 12: 149-162, 1998.[Abstract/Free Full Text]
  30. Ryan H. E., Lo J., Johnson R. S. HIF-1 {alpha} is required for solid tumor formation and embryonic vascularization. EMBO J., 17: 3005-3015, 1998.[Abstract]
  31. Zhong H., Chiles K., Feldser D., Laughner E., Hanrahan C., Georgescu M. M., Simons J. W., Semenza G. L. Modulation of hypoxia-inducible factor 1{alpha} expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res., 60: 1541-1545, 2000.[Abstract/Free Full Text]
  32. Zundel W., Schindler C., Haas-Kogan D., Koong A., Kaper F., Chen E., Gottschalk A. R., Ryan H. E., Johnson R. S., Jefferson A. B., Stokoe D., Giaccia A. J. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev., 14: 391-396, 2000.[Abstract/Free Full Text]
  33. Feldser D., Agani F., Iyer N. V., Pak B., Ferreira G., Semenza G. L. Reciprocal positive regulation of hypoxia-inducible factor l{alpha} and insulin-like growth factor 2. Cancer Res., 59: 3915-3918, 1999.[Abstract/Free Full Text]
  34. Ramaswamy S., Nakamura N., Vazquez F., Batt D. B., Perera S., Roberts T. M., Sellers W. R. Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. Proc. Natl. Acad. Sci. USA, 96: 2110-2115, 1999.[Abstract/Free Full Text]
  35. Jiang B. H., Zheng J. Z., Vogt P. K. An essential role of phosphatidylinositol 3-kinase in myogenic differentiation. Proc. Natl. Acad. Sci. USA, 95: 14179-14183, 1998.[Abstract/Free Full Text]
  36. Jiang G., den Hertog J., Su J., Noel J., Sap J., Hunter T. Dimerization inhibits the activity of receptor-like protein-tyrosine phosphatase-{alpha}. Nature (Lond.), 401: 606-610, 1999.[Medline]
  37. Salceda S., Caro J. Hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J. Biol. Chem., 272: 22642-22647, 1997.[Abstract/Free Full Text]
  38. Ivan M., Kaelin W. G. The von Hippel-Lindau tumor suppressor protein. Curr. Opin. Genet. Dev., 11: 27-34, 2001.[Medline]
  39. Huang L. E., Gu J., Schau M., Bunn H. F. Regulation of hypoxia-inducible factor 1{alpha} is mediated by an O2- dependent degradation domain via the ubiquitin-proteasome pathway. Proc. Natl. Acad. Sci. USA, 95: 7987-7992, 1998.[Abstract/Free Full Text]
  40. Kallio P. J., Wilson W. J., O’Brien S., Makino Y., Poellinger L. Regulation of the hypoxia-inducible transcription factor 1{alpha} by the ubiquitin-proteasome pathway. J. Biol. Chem., 274: 6519-6525, 1999.[Abstract/Free Full Text]
  41. Sutter C. H., Laughner E., Semenza G. L. Hypoxia-inducible factor 1{alpha} protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations. Proc. Natl. Acad. Sci. USA, 97: 4748-4753, 2000.[Abstract/Free Full Text]
  42. Cockman M. E., Masson N., Mole D. R., Jaakkola P., Chang G. W., Clifford S. C., Maher E. R., Pugh C. W., Ratcliffe P. J., Maxwell P. H. Hypoxia inducible factor-{alpha} binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J. Biol. Chem., 275: 25733-25741, 2000.[Abstract/Free Full Text]
  43. Kamura T., Sato S., Iwai K., Czyzyk-Krzeska M., Conaway R. C., Conaway J. W. Activation of HIF1{alpha} ubiquitination by a reconstituted von Hippel- Lindau (VHL) tumor suppressor complex. Proc. Natl. Acad. Sci. USA, 97: 10430-10435, 2000.[Abstract/Free Full Text]
  44. Ohh M., Park C. W., Ivan M., Hoffman M. A., Kim T. Y., Huang L. E., Pavletich N., Chau V., Kaelin W. G. Ubiquitination of hypoxia-inducible factor requires direct binding to the ß-domain of the von Hippel-Lindau protein. Nat. Cell Biol., 2: 423-427, 2000.[Medline]
  45. Tanimoto K., Makino Y., Pereira T., Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1{alpha} by the von Hippel-Lindau tumor suppressor protein. EMBO J., 19: 4298-4309, 2000.[Abstract]
  46. Forsythe J. A., Jiang B. H., Iyer N. V., Agani F., Leung S. W., Koos R. D., Semenza G. L. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol., 16: 4604-4613, 1996.[Abstract/Free Full Text]
  47. Ali I. U., Schriml L. M., Dean M. Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J. Natl. Cancer Inst. (Bethesda), 91: 1922-1932, 1999.[Abstract/Free Full Text]
  48. Jiang B. H., Semenza G. L., Bauer C., Marti H. H. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am. J. Physiol., 271: C1172-C1180, 1996.[Abstract/Free Full Text]
  49. Hoffman E. C., Reyes H., Chu F. F., Sander F., Conley L. H., Brooks B. A., Hankinson O. Cloning of a factor required for activity of the Ah (dioxin) receptor. Science (Wash. DC), 252: 954-958, 1991.[Abstract/Free Full Text]
  50. Reisz-Porszasz S., Probst M. R., Fukunaga B. N., Hankinson O. Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT). Mol. Cell. Biol., 14: 6075-6086, 1994.[Abstract/Free Full Text]
  51. Probst M. R., Reisz-Porszasz S., Agbunag R. V., Ong M. S., Hankinson O. Role of the aryl hydrocarbon receptor nuclear translocator protein in aryl hydrocarbon (dioxin) receptor action. Mol. Pharmacol, 44: 511-518, 1993.[Abstract/Free Full Text]



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Mol. Cancer Ther., November 1, 2007; 6(11): 2900 - 2908.
[Abstract] [Full Text] [PDF]


Home page
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The transcription factor HIF-1{alpha} plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis
Genes & Dev., May 1, 2007; 21(9): 1037 - 1049.
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Carcinogenesis, April 1, 2007; 28(4): 858 - 864.
[Abstract] [Full Text] [PDF]


Home page
Molecular Cancer TherapeuticsHome page
B. Fu, J. Xue, Z. Li, X. Shi, B.-H. Jiang, and J. Fang
Chrysin inhibits expression of hypoxia-inducible factor-1{alpha} through reducing hypoxia-inducible factor-1{alpha} stability and inhibiting its protein synthesis
Mol. Cancer Ther., January 1, 2007; 6(1): 220 - 226.
[Abstract] [Full Text] [PDF]


Home page
CarcinogenesisHome page
Q. Zhou, L.-Z. Liu, B. Fu, X. Hu, X. Shi, J. Fang, and B.-H. Jiang
Reactive oxygen species regulate insulin-induced VEGF and HIF-1{alpha} expression through the activation of p70S6K1 in human prostate cancer cells
Carcinogenesis, January 1, 2007; 28(1): 28 - 37.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
H. Tanaka, M. Yamamoto, N. Hashimoto, M. Miyakoshi, S. Tamakawa, M. Yoshie, Y. Tokusashi, K. Yokoyama, Y. Yaginuma, and K. Ogawa
Hypoxia-Independent Overexpression of Hypoxia-Inducible Factor 1{alpha} as an Early Change in Mouse Hepatocarcinogenesis
Cancer Res., December 1, 2006; 66(23): 11263 - 11270.
[Abstract] [Full Text] [PDF]


Home page
IOVSHome page
Q. Ebrahem, A. Minamoto, G. Hoppe, B. Anand-Apte, and J. E. Sears
Triamcinolone Acetonide Inhibits IL-6- and VEGF-Induced Angiogenesis Downstream of the IL-6 and VEGF Receptors
Invest. Ophthalmol. Vis. Sci., November 1, 2006; 47(11): 4935 - 4941.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
X.-H. Peng, P. Karna, Z. Cao, B.-H. Jiang, M. Zhou, and L. Yang
Cross-talk between Epidermal Growth Factor Receptor and Hypoxia-inducible Factor-1{alpha} Signal Pathways Increases Resistance to Apoptosis by Up-regulating Survivin Gene Expression
J. Biol. Chem., September 8, 2006; 281(36): 25903 - 25914.
[Abstract] [Full Text] [PDF]


Home page
Endocr Relat CancerHome page
K S Kimbro and J W Simons
Hypoxia-inducible factor-1 in human breast and prostate cancer.
Endocr. Relat. Cancer, September 1, 2006; 13(3): 739 - 749.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Renal Physiol.Home page
V. H. Haase
Hypoxia-inducible factors in the kidney
Am J Physiol Renal Physiol, August 1, 2006; 291(2): F271 - F281.
[Abstract] [Full Text] [PDF]


Home page
Mol Cancer ResHome page
N. Pore, Z. Jiang, H.-K. Shu, E. Bernhard, G. D. Kao, and A. Maity
Akt1 Activation Can Augment Hypoxia-Inducible Factor-1{alpha} Expression by Increasing Protein Translation through a Mammalian Target of Rapamycin-Independent Pathway
Mol. Cancer Res., July 1, 2006; 4(7): 471 - 479.
[Abstract] [Full Text] [PDF]


Home page
Biol. Reprod.Home page
P.A. Elustondo, G.E. Hannigan, I. Caniggia, and D.J. MacPhee
Integrin-Linked Kinase (ILK) Is Highly Expressed in First Trimester Human Chorionic Villi and Regulates Migration of a Human Cytotrophoblast-Derived Cell Line
Biol Reprod, May 1, 2006; 74(5): 959 - 968.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
J. Ding, J. Li, J. Chen, H. Chen, W. Ouyang, R. Zhang, C. Xue, D. Zhang, S. Amin, D. Desai, et al.
Effects of Polycyclic Aromatic Hydrocarbons (PAHs) on Vascular Endothelial Growth Factor Induction through Phosphatidylinositol 3-Kinase/AP-1-dependent, HIF-1{alpha}-independent Pathway
J. Biol. Chem., April 7, 2006; 281(14): 9093 - 9100.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
N. Pore, Z. Jiang, A. Gupta, G. Cerniglia, G. D. Kao, and A. Maity
EGFR Tyrosine Kinase Inhibitors Decrease VEGF Expression by Both Hypoxia-Inducible Factor (HIF)-1-Independent and HIF-1-Dependent Mechanisms.
Cancer Res., March 15, 2006; 66(6): 3197 - 3204.
[Abstract] [Full Text] [PDF]


Home page
Hum Reprod UpdateHome page
J.L. James, P.R. Stone, and L.W. Chamley
The regulation of trophoblast differentiation by oxygen in the first trimester of pregnancy
Hum. Reprod. Update, March 1, 2006; 12(2): 137 - 144.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
D. T. Dang, F. Chen, L. B. Gardner, J. M. Cummins, C. Rago, F. Bunz, S. V. Kantsevoy, and L. H. Dang
Hypoxia-Inducible Factor-1{alpha} Promotes Nonhypoxia-Mediated Proliferation in Colon Cancer Cells and Xenografts
Cancer Res., February 1, 2006; 66(3): 1684 - 1693.
[Abstract] [Full Text] [PDF]


Home page
J. Cell Sci.Home page
A. Dekanty, S. Lavista-Llanos, M. Irisarri, S. Oldham, and P. Wappner
The insulin-PI3K/TOR pathway induces a HIF-dependent transcriptional response in Drosophila by promoting nuclear localization of HIF-{alpha}/Sima
J. Cell Sci., December 1, 2005; 118(23): 5431 - 5441.
[Abstract] [Full Text] [PDF]


Home page
Proc. Natl. Acad. Sci. USAHome page
A. K. Neumann, J. Yang, M. P. Biju, S. K. Joseph, R. S. Johnson, V. H. Haase, B. D. Freedman, and L. A. Turka
Hypoxia inducible factor 1{alpha} regulates T cell receptor signal transduction
PNAS, November 22, 2005; 102(47): 17071 - 17076.
[Abstract] [Full Text] [PDF]


Home page
Clin. Cancer Res.Home page
L. Hu, J. Hofmann, and R. B. Jaffe
Phosphatidylinostol 3-Kinase Mediates Angiogenesis and Vascular Permeability Associated with Ovarian Carcinoma
Clin. Cancer Res., November 15, 2005; 11(22): 8208 - 8212.
[Abstract] [Full Text] [PDF]


Home page
Clin. Cancer Res.Home page
H. Dalwadi, K. Krysan, N. Heuze-Vourc'h, M. Dohadwala, D. Elashoff, S. Sharma, N. Cacalano, A. Lichtenstein, and S. Dubinett
Cyclooxygenase-2-Dependent Activation of Signal Transducer and Activator of Transcription 3 by Interleukin-6 in Non-Small Cell Lung Cancer
Clin. Cancer Res., November 1, 2005; 11(21): 7674 - 7682.
[Abstract] [Full Text] [PDF]


Home page
Sci SignalHome page
R. H. Wenger, D. P. Stiehl, and G. Camenisch
Integration of Oxygen Signaling at the Consensus HRE
Sci. Signal., October 18, 2005; 2005(306): re12 - re12.
[Abstract] [Full Text] [PDF]


Home page
Molecular Cancer TherapeuticsHome page
Q. Zhang, X. Tang, Q. Y. Lu, Z. F. Zhang, J. Brown, and A. D. Le
Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1{alpha} and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells
Mol. Cancer Ther., October 1, 2005; 4(10): 1465 - 1474.
[Abstract] [Full Text] [PDF]


Home page
Mol. Pharmacol.Home page
M. L. Yen, J. L. Su, C. L. Chien, K. W. Tseng, C. Y. Yang, W. F. Chen, C. C. Chang, and M. L. Kuo
Diosgenin Induces Hypoxia-Inducible Factor-1 Activation and Angiogenesis through Estrogen Receptor-Related Phosphatidylinositol 3-kinase/Akt and p38 Mitogen-Activated Protein Kinase Pathways in Osteoblasts
Mol. Pharmacol., October 1, 2005; 68(4): 1061 - 1073.
[Abstract] [Full Text] [PDF]


Home page
JNCI J Natl Cancer InstHome page
J.-Y. Han, S. H. Oh, F. Morgillo, J. N. Myers, E. Kim, W. K. Hong, and H.-Y. Lee
Hypoxia-inducible Factor 1{alpha} and Antiangiogenic Activity of Farnesyltransferase Inhibitor SCH66336 in Human Aerodigestive Tract Cancer
J Natl Cancer Inst, September 7, 2005; 97(17): 1272 - 1286.
[Abstract] [Full Text] [PDF]


Home page
Mol. Pharmacol.Home page
L.-Z. Liu, J. Fang, Q. Zhou, X. Hu, X. Shi, and B.-H. Jiang
Apigenin Inhibits Expression of Vascular Endothelial Growth Factor and Angiogenesis in Human Lung Cancer Cells: Implication of Chemoprevention of Lung Cancer
Mol. Pharmacol., September 1, 2005; 68(3): 635 - 643.
[Abstract] [Full Text] [PDF]


Home page
Br J AnaesthHome page
E. Lucchinetti, R. da Silva, T. Pasch, M. C. Schaub, and M. Zaugg
Anaesthetic preconditioning but not postconditioning prevents early activation of the deleterious cardiac remodelling programme: evidence of opposing genomic responses in cardioprotection by pre- and postconditioning
Br. J. Anaesth., August 1, 2005; 95(2): 140 - 152.
[Abstract] [Full Text] [PDF]


Home page
Clin. Cancer Res.Home page
G. J. Kelloff, J. M. Hoffman, B. Johnson, H. I. Scher, B. A. Siegel, E. Y. Cheng, B. D. Cheson, J. O'Shaughnessy, K. Z. Guyton, D. A. Mankoff, et al.
Progress and Promise of FDG-PET Imaging for Cancer Patient Management and Oncologic Drug Development
Clin. Cancer Res., April 15, 2005; 11(8): 2785 - 2808.
[Abstract] [Full Text] [PDF]


Home page
FASEB J.Home page
J. Fang, C. Xia, Z. Cao, J. Z. Zheng, E. Reed, and B.-H. Jiang
Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways
FASEB J, March 1, 2005; 19(3): 342 - 353.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
R. Blum, J. Jacob-Hirsch, N. Amariglio, G. Rechavi, and Y. Kloog
Ras Inhibition in Glioblastoma Down-regulates Hypoxia-Inducible Factor-1{alpha}, Causing Glycolysis Shutdown and Cell Death
Cancer Res., February 1, 2005; 65(3): 999 - 1006.
[Abstract] [Full Text] [PDF]


Home page
J. Appl. Physiol.Home page
E. V. Gerasimovskaya, D. A. Tucker, and K. R. Stenmark
Activation of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin is necessary for hypoxia-induced pulmonary artery adventitial fibroblast proliferation
J Appl Physiol, February 1, 2005; 98(2): 722 - 731.
[Abstract] [Full Text] [PDF]


Home page
Clin. Cancer Res.Home page
M.-H. Li, Z.-H. Miao, W.-F. Tan, J.-M. Yue, C. Zhang, L.-P. Lin, X.-W. Zhang, and J. Ding
Pseudolaric Acid B Inhibits Angiogenesis and Reduces Hypoxia-Inducible Factor 1{alpha} by Promoting Proteasome-Mediated Degradation
Clin. Cancer Res., December 15, 2004; 10(24): 8266 - 8274.
[Abstract] [Full Text] [PDF]


Home page
Clin. Cancer Res.Home page
G. J. Hutchison, H. R. Valentine, J. A. Loncaster, S. E. Davidson, R. D. Hunter, S. A. Roberts, A. L. Harris, I. J. Stratford, P. M. Price, and C. M. L. West
Hypoxia-Inducible Factor 1{alpha} Expression as an Intrinsic Marker of Hypoxia: Correlation with Tumor Oxygen, Pimonidazole Measurements, and Outcome in Locally Advanced Carcinoma of the Cervix
Clin. Cancer Res., December 15, 2004; 10(24): 8405 - 8412.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
H. D. Skinner, J. Z. Zheng, J. Fang, F. Agani, and B.-H. Jiang
Vascular Endothelial Growth Factor Transcriptional Activation Is Mediated by Hypoxia-inducible Factor 1{alpha}, HDM2, and p70S6K1 in Response to Phosphatidylinositol 3-Kinase/AKT Signaling
J. Biol. Chem., October 29, 2004; 279(44): 45643 - 45651.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
D. Z. Qian, X. Wang, S. K. Kachhap, Y. Kato, Y. Wei, L. Zhang, P. Atadja, and R. Pili
The Histone Deacetylase Inhibitor NVP-LAQ824 Inhibits Angiogenesis and Has a Greater Antitumor Effect in Combination with the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor PTK787/ZK222584
Cancer Res., September 15, 2004; 64(18): 6626 - 6634.
[Abstract] [Full Text] [PDF]


Home page
Mol. Pharmacol.Home page
S. Lin, S.-C. Tsai, C.-C. Lee, B.-W. Wang, J.-Y. Liou, and K.-G. Shyu
Berberine Inhibits HIF-1{alpha} Expression via Enhanced Proteolysis
Mol. Pharmacol., September 1, 2004; 66(3): 612 - 619.
[Abstract] [Full Text] [PDF]


Home page
Clin. Cancer Res.Home page
Z. Cao, J. Fang, C. Xia, X. Shi, and B.-H. Jiang
trans-3,4,5'-Trihydroxystibene Inhibits Hypoxia-Inducible Factor 1{alpha} and Vascular Endothelial Growth Factor Expression in Human Ovarian Cancer Cells
Clin. Cancer Res., August 1, 2004; 10(15): 5253 - 5263.
[Abstract] [Full Text] [PDF]


Home page
Mol. Pharmacol.Home page
J. Fang, Z. Cao, Y. C. Chen, E. Reed, and B.-H. Jiang
9-{beta}-D-Arabinofuranosyl-2-fluoroadenine Inhibits Expression of Vascular Endothelial Growth Factor through Hypoxia-Inducible Factor-1 in Human Ovarian Cancer Cells
Mol. Pharmacol., July 1, 2004; 66(1): 178 - 186.
[Abstract] [Full Text] [PDF]


Home page
CarcinogenesisHome page
C. Segrelles, S. Ruiz, M. Santos, J. Martinez-Palacio, M. F. Lara, and J. M. Paramio
Akt mediates an angiogenic switch in transformed keratinocytes
Carcinogenesis, July 1, 2004; 25(7): 1137 - 1147.
[Abstract] [Full Text] [PDF]


Home page
Molecular Cancer TherapeuticsHome page
G. Powis and L. Kirkpatrick
Hypoxia inducible factor-1{alpha} as a cancer drug target
Mol. Cancer Ther., May 1, 2004; 3(5): 647 - 654.
[Abstract] [Full Text] [PDF]


Home page
Genes Dev.Home page
L. Bemis, D. A. Chan, C. V. Finkielstein, L. Qi, P. D. Sutphin, X. Chen, K. Stenmark, A. J. Giaccia, and W. Zundel
Distinct aerobic and hypoxic mechanisms of HIF-{alpha} regulation by CSN5
Genes & Dev., April 1, 2004; 18(7): 739 - 744.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
G. Hopfl, O. Ogunshola, and M. Gassmann
HIFs and tumors--causes and consequences
Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2004; 286(4): R608 - R623.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
N. C Chi and J. S Karliner
Molecular determinants of responses to myocardial ischemia/reperfusion injury: focus on hypoxia-inducible and heat shock factors
Cardiovasc Res, February 15, 2004; 61(3): 437 - 447.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
J. Li, G. Davidson, Y. Huang, B.-H. Jiang, X. Shi, M. Costa, and C. Huang
Nickel Compounds Act through Phosphatidylinositol-3-kinase/Akt-Dependent, p70S6k-Independent Pathway to Induce Hypoxia Inducible Factor Transactivation and Cap43 Expression in Mouse Epidermal Cl41 Cells
Cancer Res., January 1, 2004; 64(1): 94 - 101.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
T. T.-L. Tang and L. A. Lasky
The Forkhead Transcription Factor FOXO4 Induces the Down-regulation of Hypoxia-inducible Factor 1{alpha} by a von Hippel-Lindau Protein-independent Mechanism
J. Biol. Chem., August 8, 2003; 278(32): 30125 - 30135.
[Abstract] [Full Text] [PDF]


Home page
Molecular Cancer TherapeuticsHome page
D. C. Lev, M. Ruiz, L. Mills, E. C. McGary, J. E. Price, and M. Bar-Eli
Dacarbazine Causes Transcriptional Up-Regulation of Interleukin 8 and Vascular Endothelial Growth Factor in Melanoma Cells: A Possible Escape Mechanism from Chemotherapy
Mol. Cancer Ther., August 1, 2003; 2(8): 753 - 763.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
L. Zhang, N. Yang, D. Katsaros, W. Huang, J.-W. Park, S. Fracchioli, C. Vezzani, I. A. Rigault de la Longrais, W. Yao, S. C. Rubin, et al.
The Oncogene Phosphatidylinositol 3'-Kinase Catalytic Subunit {alpha} Promotes Angiogenesis via Vascular Endothelial Growth Factor in Ovarian Carcinoma
Cancer Res., July 15, 2003; 63(14): 4225 - 4231.
[Abstract] [Full Text] [PDF]


Home page
Clin. Cancer Res.Home page
N. J. Mabjeesh, M. T. Willard, C. E. Frederickson, H. Zhong, and J. W. Simons
Androgens Stimulate Hypoxia-inducible Factor 1 Activation via Autocrine Loop of Tyrosine Kinase Receptor/Phosphatidylinositol 3'-Kinase/Protein Kinase B in Prostate Cancer Cells
Clin. Cancer Res., July 1, 2003; 9(7): 2416 - 2425.
[Abstract] [Full Text] [PDF]


Home page
J. Cell Sci.Home page
S. Turcotte, R. R. Desrosiers, and R. Beliveau
HIF-1{alpha} mRNA and protein upregulation involves Rho GTPase expression during hypoxia in renal cell carcinoma
J. Cell Sci., June 1, 2003; 116(11): 2247 - 2260.
[Abstract] [Full Text] [PDF]


Home page
Molecular Cancer TherapeuticsHome page
S. J. Welsh, R. R. Williams, A. Birmingham, D. J. Newman, D. L. Kirkpatrick, and G. Powis
The Thioredoxin Redox Inhibitors 1-Methylpropyl 2-Imidazolyl Disulfide and Pleurotin Inhibit Hypoxia-induced Factor 1{alpha} and Vascular Endothelial Growth Factor Formation
Mol. Cancer Ther., March 1, 2003; 2(3): 235 - 243.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
M. C. A. Duyndam, S. T. M. Hulscher, E. van der Wall, H. M. Pinedo, and E. Boven
Evidence for a Role of p38 Kinase in Hypoxia-inducible Factor 1-independent Induction of Vascular Endothelial Growth Factor Expression by Sodium Arsenite
J. Biol. Chem., February 21, 2003; 278(9): 6885 - 6895.
[Abstract] [Full Text] [PDF]


Home page
Mol Cancer ResHome page
K. D. Burroughs, J. Oh, J. C. Barrett, and R. P. DiAugustine
Phosphatidylinositol 3-Kinase and Mek1/2 Are Necessary for Insulin-Like Growth Factor-I-Induced Vascular Endothelial Growth Factor Synthesis in Prostate Epithelial Cells: A Role for Hypoxia-Inducible Factor-1?
Mol. Cancer Res., February 1, 2003; 1(4): 312 - 322.
[Abstract] [Full Text] [PDF]


Home page
BloodHome page
T. Kietzmann, A. Samoylenko, U. Roth, and K. Jungermann
Hypoxia-inducible factor-1 and hypoxia response elements mediate the induction of plasminogen activator inhibitor-1 gene expression by insulin in primary rat hepatocytes
Blood, February 1, 2003; 101(3): 907 - 914.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
N. Gao, B.-H. Jiang, S. S. Leonard, L. Corum, Z. Zhang, J. R. Roberts, J. Antonini, J. Z. Zheng, D. C. Flynn, V. Castranova, et al.
p38 Signaling-mediated Hypoxia-inducible Factor 1alpha and Vascular Endothelial Growth Factor Induction by Cr(VI) in DU145 Human Prostate Carcinoma Cells
J. Biol. Chem., November 15, 2002; 277(47): 45041 - 45048.
[Abstract] [Full Text] [PDF]


Home page
Mol. Cell. Biol.Home page
C. C. Hudson, M. Liu, G. G. Chiang, D. M. Otterness, D. C. Loomis, F. Kaper, A. J. Giaccia, and R. T. Abraham
Regulation of Hypoxia-Inducible Factor 1{alpha} Expression and Function by the Mammalian Target of Rapamycin
Mol. Cell. Biol., October 15, 2002; 22(20): 7004 - 7014.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
S. J. Welsh, W. T. Bellamy, M. M. Briehl, and G. Powis
The Redox Protein Thioredoxin-1 (Trx-1) Increases Hypoxia-inducible Factor 1{alpha} Protein Expression: Trx-1 Overexpression Results in Increased Vascular Endothelial Growth Factor Production and Enhanced Tumor Angiogenesis
Cancer Res., September 1, 2002; 62(17): 5089 - 5095.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
N. Gao, M. Ding, J. Z. Zheng, Z. Zhang, S. S. Leonard, K. J. Liu, X. Shi, and B.-H. Jiang
Vanadate-induced Expression of Hypoxia-inducible Factor 1{alpha} and Vascular Endothelial Growth Factor through Phosphatidylinositol 3-Kinase/Akt Pathway and Reactive Oxygen Species
J. Biol. Chem., August 30, 2002; 277(35): 31963 - 31971.
[Abstract] [Full Text] [PDF]


Home page
Sci SignalHome page
K. A. Seta, Z. Spicer, Y. Yuan, G. Lu, and D. E. Millhorn
Responding to Hypoxia: Lessons From a Model Cell Line
Sci. Signal., August 20, 2002; 2002(146): re11 - re11.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
V. Seshadri, P. L. Fox, and C. K. Mukhopadhyay
Dual Role of Insulin in Transcriptional Regulation of the Acute Phase Reactant Ceruloplasmin
J. Biol. Chem., August 2, 2002; 277(31): 27903 - 27911.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
C. Treins, S. Giorgetti-Peraldi, J. Murdaca, G. L. Semenza, and E. Van Obberghen
Insulin Stimulates Hypoxia-inducible Factor 1 through a Phosphatidylinositol 3-Kinase/Target of Rapamycin-dependent Signaling Pathway
J. Biol. Chem., August 2, 2002; 277(31): 27975 - 27981.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
S. Kaluz, M. Kaluzova, A. Chrastina, P. L. Olive, S. Pastorekova, J. Pastorek, M. I. Lerman, and E. J. Stanbridge
Lowered Oxygen Tension Induces Expression of the Hypoxia Marker MN/Carbonic Anhydrase IX in the Absence of Hypoxia-inducible Factor 1{alpha} Stabilization: A Role for Phosphatidylinositol 3'-Kinase
Cancer Res., August 1, 2002; 62(15): 4469 - 4477.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
A. M. Arsham, D. R. Plas, C. B. Thompson, and M. C. Simon
Phosphatidylinositol 3-Kinase/Akt Signaling Is Neither Required for Hypoxic Stabilization of HIF-1{alpha} nor Sufficient for HIF-1-dependent Target Gene Transcription
J. Biol. Chem., April 26, 2002; 277(17): 15162 - 15170.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
M. Alvarez-Tejado, A. Alfranca, J. Aragones, A. Vara, M. O. Landazuri, and L. del Peso
Lack of Evidence for the Involvement of the Phosphoinositide 3-Kinase/Akt Pathway in the Activation of Hypoxia-inducible Factors by Low Oxygen Tension
J. Biol. Chem., April 19, 2002; 277(16): 13508 - 13517.
[Abstract] [Full Text] [PDF]


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