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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
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but not of HIF-1ß in human cancer cell lines. This specific elevation of HIF-1 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 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 but not that of HIF-1ß. In contrast to the HIF-1 protein, the level of HIF-1 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 |
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TOPAbstractIntroductionResultsDiscussionMaterials and MethodsReferences |
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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 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 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 but not HIF-1ß protein. Inhibition of PI3K activity by LY294002 or wortmannin or wild-type PTEN reduces the levels of HIF-1 but not the levels of HIF-1ß. However, PI3K signaling does not significantly alter the steady-state levels of HIF-1 mRNA, suggesting that it affects expression of HIF-1 posttranscriptionally. While this work was in progress, three reports appeared that also showed regulation of HIF-1 by the PI3K/PTEN/Akt/mTor pathway (31, 32, 33)
. Our studies confirm and expand the results of these earlier investigations.
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Results |
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TOPAbstractIntroductionResultsDiscussionMaterials and MethodsReferences |
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in Cancer Cell Lines.
. Insulin induced high levels of HIF-1 expression in ACHN, DU145, and PC-3 cells and a lower level of HIF-1 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. 1
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 and HIF-1ß, and insulin elevated the levels of HIF-1 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 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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. 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 by insulin and at higher concentrations reduced HIF-1 levels below basal values (Fig. 2)
. HIF-1 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 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, and LY294002 and wortmannin strongly inhibited HIF-1 expression in the presence of EGF (Fig. 3)
. In DU145 cells that have low levels of HIF-1, EGF caused a substantial up-regulation, and the PI3K inhibitors reduced EGF-induced HIF-1 expression significantly. Total cell extracts gave similar results for HIF-1 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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mRNA Levels. 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)
. In contrast to the levels of HIF-1 protein, the levels of HIF-1 mRNA in DU145 cells were not induced by EGF or insulin and were not reduced by the PI3K inhibitor LY294002 (Fig. 4B)
. In the PTEN-negative PC-3 cells, HIF-1 mRNA was modestly induced by EGF and insulin, and this induction was inhibited by the PI3K inhibitor LY294002 (Fig. 4A)
. However, the reduction of HIF-1 mRNA levels by LY294002 was minor when compared with the changes of HIF-1 protein levels. In PC-3 cells, expression of the HIF-1 protein was extinguished by 10 µM LY294002 (Figs. 2
and 3
). The difference in response of HIF-1 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 mRNA are not affected by PI3K signaling; (b) in PC-3 cells, HIF-1 mRNA levels are slightly affected by PI3K activity; and (c) insulin and EGF increase levels of HIF-1 protein expression mainly at the posttranscriptional level.
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. are constitutively high (Fig. 1)
. To test the role of PTEN in the regulation of HIF-1, 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 protein levels (Fig. 5)
. 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 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 levels.
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. Cotransfection of PTEN or of a dominant negative construct of PI3K, p85
iSH2N (35)
, also inhibited reporter activity in three cell lines (PC-3, U373, and P19; Fig. 6B
). 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 construct, HIF-1NBAB (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)
, 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 (31)
.
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Discussion |
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protein (Figs. 1
2
3)
and positively regulates HIF-1-mediated transcription of VEGF in diverse tumor cell lines (Fig. 6)
. These observations suggest that PI3K and (by implication) its downstream target Akt affect angiogenesis by controlling the levels of HIF-1.
Several lines of evidence support the conclusion that PI3K signals elevate levels of HIF-1 protein in the cells. First, treatment with insulin or EGF results in higher levels of HIF-1 in several human cancer cell lines (Fig. 1)
. Signals from insulin or EGF are processed by PI3K and hence place PI3K in control of HIF-1. Second, the insulin- or EGF-induced increase in HIF-1 can be largely or completely abolished by the PI3K inhibitors LY294002 or wortmannin as well as by overexpression of PTEN (Figs. 2
, 3
, and 5
). These results demonstrate a requirement for PI3K in the increase of HIF-1. Third, insulin or EGF induces higher levels of HIF-1, but not of HIF-1ß (Figs. 1
2
3)
. 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 and that LY29A002 inhibits this induction (31)
.
Activation of PI3K leads to increased HIF-1 protein levels but not to a corresponding increase in the steady-state levels of HIF-1 mRNA (Fig. 4)
. Therefore, PI3K regulates HIF-1 mainly by altering either the stability of the HIF-1 protein or the efficiency of HIF-1 mRNA translation. Existing data favor the former alternative. A recent report (32)
provides strong evidence that Akt stabilizes HIF-1, consistent with results of the current study. The stability of the HIF-1 protein is regulated by the proteasomal degradation pathway (37, 38, 39, 40, 41)
. HIF-1 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 levels because pVHL directs the oxygen-dependent ubiquitination of HIF-1 (42, 43, 44, 45)
. Stabilization of HIF-1 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 and pVHL. This proposal on the effect of PI3K signaling on pVHL function can be tested experimentally. The control of HIF-1 levels appears to be an important aspect of pVHL function. All pVHL mutants linked to the VHL syndrome fail to regulate HIF-1 (38)
. Tumors in VHL patients are highly vascularized, possibly as a result of the overexpression of HIF-1-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 regulates VEGF transcription by binding to the VEGF promoter (46)
. The current study shows that HIF-1 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)
. These results identify HIF-1 as a critical component in PI3K/Akt-mediated angiogenesis and suggest that changes in the level of the HIF-1 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/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 heterodimerizes only with HIF-1ß, and HIF-1 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 but not of HIF-1ß points to an important aspect of signal specificity in the PI3K cascade allowing an increase in HIF-1/HIF-1ß heterodimers but not in heterodimers of HIF-ß with other transcription factors. This suggests that chemotherapeutic agents could selectively target HIF-1.
In summary, we demonstrated that the levels of HIF-1 are controlled by PI3K and may represent a critical component in PI3K/Akt-dependent angiogenesis and tumorigenesis. HIF-1 and its regulatory signals emerge as potential targets for therapeutic intervention in cancer.
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Materials and Methods |
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TOPAbstractIntroductionResultsDiscussionMaterials and MethodsReferences |
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DNA Constructs.
The dominant negative form of PI3K, p85iSH2N, 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-1NBAB, 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 (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 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.
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Acknowledgments |
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Footnotes |
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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. 
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.
3 Recipient of a fellowship from the American Cancer Society. Present address: Molecular Endocrinology and Metabolic Disorders, Merck & Co., Inc., Rahway, NJ 07065.
4 Recipient of a Pioneer Fund Fellowship.
5 A Frank and Else Schilling American Cancer Society Research Professor.
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
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.
Received for publication 3/ 1/01. Revision received 5/18/01. Accepted for publication 5/22/01.
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J. Fang, Q. Zhou, L.-Z. Liu, C. Xia, X. Hu, X. Shi, and B.-H. Jiang Apigenin inhibits tumor angiogenesis through decreasing HIF-1{alpha} and VEGF expression Carcinogenesis, April 1, 2007; 28(4): 858 - 864. [Abstract] [Full Text] [PDF]
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 F. Wang, S. S. Li, R. Segersvard, L. Strommer, K.-G. Sundqvist, J. Holgersson, and J. Permert Hypoxia Inducible Factor-1 Mediates Effects of Insulin on Pancreatic Cancer Cells and Disturbs Host Energy Homeostasis Am. J. Pathol., February 1, 2007; 170(2): 469 - 477. [Abstract] [Full Text] [PDF]
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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]
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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]
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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]
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 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]
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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]
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 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]
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 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]
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 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]
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 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]
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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]
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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]
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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]
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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]
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 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]
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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]
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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]
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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]
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 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]
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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]
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 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]
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 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]
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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]
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 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]
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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]
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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]
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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]
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 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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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 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]
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 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]
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U. Roth, K. Curth, T. G. Unterman, and T. Kietzmann The Transcription Factors HIF-1 and HNF-4 and the Coactivator p300 Are Involved in Insulin-regulated Glucokinase Gene Expression via the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway J. Biol. Chem., January 23, 2004; 279(4): 2623 - 2631. [Abstract] [Full Text] [PDF]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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 S. Ahmad, A. Ahmad, E. Gerasimovskaya, K. R. Stenmark, C. B. Allen, and C. W. White Hypoxia Protects Human Lung Microvascular Endothelial and Epithelial-like Cells against Oxygen Toxicity: Role of Phosphatidylinositol 3-Kinase Am. J. Respir. Cell Mol. Biol., February 1, 2003; 28(2): 179 - 187. [Abstract] [Full Text] [PDF]
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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]
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 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]
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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]
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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]
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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]
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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 1alpha and Vascular Endothelial Growth Factor through Phosphatidylinositol 3-Kinase/Akt Pathway and Reactive Oxygen Species J. Biol. Chem., August 23, 2002; 277(35): 31963 - 31971. [Abstract] [Full Text] [PDF]
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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]
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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]
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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., July 26, 2002; 277(31): 27903 - 27911. [Abstract] [Full Text] [PDF]
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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., July 26, 2002; 277(31): 27975 - 27981. [Abstract] [Full Text] [PDF]
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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-1alpha nor Sufficient for HIF-1-dependent Target Gene Transcription J. Biol. Chem., April 19, 2002; 277(17): 15162 - 15170. [Abstract] [Full Text] [PDF]
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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 12, 2002; 277(16): 13508 - 13517. [Abstract] [Full Text] [PDF]
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