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Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Department of Medicine, Genetics, Cancer Center, and Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
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Abstract |
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 TOP Abstract IntroductionResultsDiscussionMaterials and MethodsReferences |
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Introduction |
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TOPAbstractIntroductionResultsDiscussionMaterials and MethodsReferences |
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-prothymosin (7)
, ornithine decarboxylase (ODC) (8)
, MrDb (9)
, ECA39 (10)
, and cdc25A (11)
. c-Myc may also act as a transcriptional repressor of C/EBP (12
, 4)
, cyclin D1 (13)
, the adenovirus 5 major-late promoter (4)
, thrombospondin-1 (14)
, and gadd45 (15)
. The mechanism of repression by c-Myc remains unclear. We recently reported (16) that the down-regulation of c-myc expression may be a required late step in growth arrest following phorbol ester TPA3 exposure of (TPA-sensitive) epithelial cancer cells. The growth arrest of the TPA-sensitive SkBr3 human breast cancer and LNCaP human prostate cancer cells was associated with the induction of expression of the cell cycle inhibitor p21WAF1/CIP1. p21 inhibits cell cycle progression by binding cyclin-cyclin dependent kinases and inhibiting their kinase activity (17) as well as by binding to the proliferating cell nuclear antigen PCNA, thereby inhibiting processive DNA synthesis (18) .
Because p21 was strongly induced in TPA-treated SkBr3 cells, and because constitutive c-Myc overexpression in selected SkBr3 cells conferred resistance to TPA (16) , we hypothesized that the inhibition of p21 expression may be required for c-Myc deregulation of growth arrest and for its effect to induce DNA synthesis in such quiescent cells.
We generated a c-Myc-expressing adenovirus (Ad-cMyc) to more easily study the effects of c-Myc protein in human cells. We show that an Ad-cMyc infection of either SkBr3 or LNCaP cells can overcome TPA-induced growth arrest. Interestingly, c-Myc overexpression significantly inhibited p21 expression in cells induced to enter into S phase. We explored the significance of this inhibition by examining the kinetics of p21 expression in Ad-cMyc as compared with Ad-E2F-1-infected cells. We further investigated the mechanism of this inhibition and found evidence for transcriptional repression of p21 expression by c-Myc. Ad-p21/Ad-cMyc coinfection of SkBr3 cells revealed that p21-mediated growth arrest was dominant over c-Myc’s effect to promote DNA synthesis. The results suggest that the inhibition of p21 expression may contribute to c-Myc-dependent S-phase entry, possibly in cells in which growth arrest is p21-dependent.
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Results |
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TOPAbstractIntroductionResultsDiscussionMaterials and MethodsReferences |
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shows that human c-Myc protein is easily detected by Western analysis after infection of normal human lung fibroblasts (WI38) as well as human breast (SkBr3), ovarian (SkOV3), lung (H460), and colon (SW480, HCT116) cancer cells. The mobility of the exogenous c-Myc coincided with that of the endogenous c-Myc protein (Fig. 1A
, compare Ad-LacZ versus Ad-cMyc-infected SkBr3 and H460 cells). Human c-Myc protein was also detected after the infection of NIH3T3 mouse fibroblasts, used initially because of the lack of cross-reactivity between the antihuman c-Myc antibody and mouse c-Myc protein. The level of c-Myc expression correlated with both adenovirus infectivity (not shown) and MOI (Fig. 1B)
. We then confirmed that the overexpression of c-Myc was primarily in the nucleus of Ad-cMyc-infected cells (Fig. 1C)
.
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. Ad-cMyc-infected and, subsequently, serum-deprived WI38 underwent massive nuclear fragmentation (Fig. 2, B and D)
as compared with Ad-LacZ-infected cells (Fig. 2, A and C)
. There are no DAPI(+) cells in Fig. 2C
because those WI38 cells were viable (same field in Fig. 2A
), and the cell membranes were not permeabilized. Thus, the c-Myc-dependent apoptosis phenotype was recapitulated after the Ad-cMyc infection of human cells. To further show that this was an effect of c-Myc overexpression in the WI38 cells, we performed immunohistochemical staining on cells infected with either Ad-cMyc or Ad-LacZ under the same conditions (Fig. 2, E and F)
. As expected, those cells infected with Ad-cMyc showed overexpression of the c-Myc protein as compared with those cells infected with Ad-LacZ. Ad-cMyc infection of WI38 cells seemed to have a small effect on DNA synthesis induction as compared with Ad-LacZ (Fig. 2G)
; the major effect after Ad-cMyc infection of WI38 cells was apoptosis (Fig. 2D)
. We further studied the effects of c-Myc overexpression on subsequent molecular events involved in cell cycle control.
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Fig. 4B
; Ref. 16
), we examined p21 protein expression levels after Ad-cMyc infection of these cells (Fig. 3A)
. We noted a significant inhibition in p21 expression in Ad-cMyc-infected as compared with either Ad-LacZ- or mock-infected TPA-arrested SkBr3 cells. There was no increase in p27 levels in TPA-treated SkBr3 cells (Fig. 3B)
.
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; Ref. 16
). After showing that the p21 protein expression levels are increased after TPA treatment, we examined the effects of Ad-cMyc infection (Fig. 3D)
. As seen in the breast cancer cell line (Fig. 3A)
, we observed a significant inhibition of p21 protein expression in the c-Myc-overexpressing TPA-treated prostate cancer cells (Fig. 3D)
.
We further investigated the kinetics of the TPA-induced arrest in SkBr3 cells (Fig. 4)
. Addition of TPA to the SkBr3 cells led to growth arrest detected as early as 12 h (Fig. 4A)
. The expected increase in p21 expression was observed by 4 h after the exposure of the cells to TPA, and this increase was sustained for at least 24 h (Fig. 4B)
. Increased p21 expression preceded inhibition of DNA synthesis after TPA treatment of SkBr3 cells.
To determine whether c-Myc overexpression could interfere with TPA-induced growth arrest, Ad-cMyc infection was used to constitutively overexpress c-Myc in SkBr3 cells (Fig. 4C)
. Ad-cMyc infection of SkBr3 cells seemed to rescue these cells from TPA-induced growth arrest (Fig. 4C
; compare Ad-cMyc- versus Ad-LacZ-infected cells). These results demonstrate in a human cancer cell line that the exogenous overexpression of c-Myc could deregulate cell cycle control, as evidenced by the induction of DNA synthesis despite the TPA-mediated growth-arrest signal. These findings also suggest that the inhibition of p21 expression may occur during abnormal c-Myc-induced S-phase entry.
In order to investigate the possibility that the effect on p21 may be simply due to the progression of cells into S phase, we compared the effects of overexpression of E2F-1 and c-Myc (Fig. 4C)
. E2F-1 overexpression also rescued the SkBr3 cells from the TPA-induced growth arrest. However, the expression of p21 was not down-regulated until the Ad-E2F-1-infected cells entered S phase (compare Fig. 4, C and D
).
To further investigate the effect of E2F-1 overexpression on inducing S-phase entry, we analyzed BrdUrd incorporation in parallel with p21 immunohistochemistry (Fig. 5)
. We observed a significant increase in BrdUrd-incorporating cells over time, whereas there was little decrease in p21 staining until 20 h postinfection. At 16 h, the majority of Ad-E2F-1-infected SkBr3 breast cancer cells incorporated BrdUrd (Fig. 5N)
while continuing to overexpress p21 protein (Fig. 5M)
. By 20 h, only a small minority of Ad-E2F-1 cells expressed p21 (Fig. 5S)
, whereas the vast majority of the cells continued to incorporate BrdUrd (Fig. 5T)
. These results are consistent with the interpretation that E2F-1 deregulation of S-phase entry probably acts downstream of p21 and that the inhibition of p21 expression in response to E2F-1 may be a consequence of cell cycle progression. These data are in contrast to the c-Myc situation in which the suppression of p21 expression seems to precede entry into S phase in Ad-cMyc-infected TPA-treated cells (Fig. 4, C and D)
. In the case of c-Myc, a clear decrease in p21 staining was observed by 16 h postinfection (Fig. 5O)
, whereas there was no sign of BrdUrd incorporation by this time point (Fig. 5P)
. These results indicate that the down-regulation of p21 expression by overexpression of c-Myc is probably not a consequence of S-phase progression but may be part of the primary mechanism by which c-Myc induces S-phase entry. We further examined the mechanism of c-Myc-dependent inhibition of p21 expression and the requirement of this inhibition for cell cycle deregulation.
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. We found that p21 mRNA levels were significantly lower in Ad-cMyc- as compared with Ad-LacZ-infected cells.
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. We found that the transfection of c-Myc repressed the transcription from the p21 promoter by two- to three-fold as compared with a control transfection driving antisense c-Myc expression. These experiments were carried out in SW480 human colon carcinoma cells because of their relatively high transfection efficiency (30–50%). To confirm that p53 DNA-binding sites are not required for repression by c-Myc, a p21-promoter fragment lacking the potential for regulation by p53 was cotransfected with c-Myc into (mutant p53-expressing) SW480 cells (Fig. 6B
, 4-Luc). The results further suggest that the inhibition of p21 expression after overexpression of c-Myc may occur in part through the repression of transcription.
Inhibition of p21WAF1/CIP1 Expression Is Required for Induction of DNA Synthesis by c-Myc.
We further examined the possibility that the inhibition of p21 expression may be required for S-phase deregulation by oncogenic c-Myc protein. We hypothesized that overriding the inhibition of p21 expression by c-Myc (by constitutively overexpressing p21) should prevent entry into S phase if this inhibition is critical for c-Myc function. Coinfection of SkBr3 cells (at identical MOIs) by Ad-cMyc and Ad-p21 resulted in the suppression of c-Myc-dependent S-phase entry (Fig. 7)
.
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Discussion |
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TOPAbstractIntroductionResultsDiscussionMaterials and MethodsReferences |
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In addition to cell cycle deregulation, the inhibition of p21 expression could lead to the loss of other p21-dependent functions in c-Myc-overexpressing cells. p21 has been found to be a potent suppressor of cellular transformation (23) , and the loss of p21 expression has been suggested to contribute to ras-(24) and E1A-induced (25) transformation. It is possible that in vivo, c-Myc may provide a signal to suppress p21 as a transformation-predisposing event that could then allow other oncogenes such as ras to complete the transformation. In some studies, p21 has been found to protect mammalian cells against apoptosis (26, 27, 28) . Thus, the loss of p21 expression could also provide a permissive cellular environment for c-Myc-induced apoptosis. p21 has also been implicated in the control of a fundamental aspect of cell cycle control, the coupling of S and M phases to ensure that cells do not reduplicate their DNA if they have not undergone mitotic division (28) . Thus, the c-Myc suppression of p21 expression could predispose c-Myc-overexpressing cells to abnormal S-M coordination.
Our results are somewhat different from recent observations in rat embryo fibroblast cells, suggesting that c-Myc alone was ineffective in inducing S phase (29) and that ras was required (but also ineffective when overexpressed alone in rat embryo fibroblast cells). One possible explanation for these differences is that our studies were carried out in human cancer cells. In this regard, it was previously shown (30) that SkBr3 cells express increased levels of the ras-related rho proteins, in particular rhoB, and are highly sensitive to growth inhibition by inhibitors of tyrosine kinase activity (31) . Thus, it is possible that in our experiments, c-Myc was sufficient to induce S-phase entry because the ras pathway may be deregulated in SkBr3 cells. Perhaps not surprisingly then, in the serum-starvation-arrested WI38 normal lung fibroblasts, there was a poor induction of DNA synthesis after Ad-cMyc infection.
A possible explanation of our results is that the inhibition of p21 expression after c-Myc overexpression may be an indirect effect of cell cycle progression. We addressed this issue by inducing S-phase entry by E2F-1-overexpression. The results in Figs. 4
and 5
suggest that there is a fundamental difference in the mechanism of cell cycle deregulation by c-Myc versus E2F-1. In TPA-arrested breast cancer cells, Ad-E2F-1 infection led to early S-phase entry (seen by 12 h in some cells; Fig. 5J
), whereas the majority of the cells overexpressed p21. By 16 h, the vast majority of Ad-E2F-1 infected cells were in S phase as assessed by BrdUrd incorporation (Fig. 5N)
and continued to overexpress p21. Only by 20 h, were p21 levels decreased in Ad-E2F-1 infected TPA-treated cells. These results suggest that in the case of E2F-1, the suppression of p21 expression is not required for deregulation of S-phase entry. In the case of c-Myc, the results demonstrate that the suppression of p21 expression occurs before S-phase entry. Thus, in TPA-sensitive cells, TPA induces a cell cycle arrest in both G1 and G24 associated with the induction of p21 (but not p27) protein expression (Figs. 3
and 4
) and the inhibition of c-Myc expression (16)
. In such situations in which growth arrest is associated with elevated p21 expression, the introduction of constitutive c-Myc overexpression: (a) deregulates the arrest; and (b) suppresses p21 expression before S-phase entry. Our results suggest that the suppression of p21 expression is an early event that follows c-Myc overexpression and argue that it may be a necessary step in cell cycle deregulation, at least in TPA-arrested p21-overexpressing SkBr3 breast cancer cells.
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Materials and Methods |
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TOPAbstractIntroductionResultsDiscussionMaterials and MethodsReferences |
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Adenovirus Preparation and Infection.
A human c-Myc-expressing Ad5 adenovirus recombinant was generated as previously described for p53 and p21 (32
, 33)
. The c-Myc cDNA was amplified from H460 total RNA by reverse transcription-PCR using the following primers and PCR conditions: forward primer 5'-ATACGCGGATCCACCATGCCCCTCAACGTT-AGCTTCAC-3'; and reverse primer 5'-GCGTATCCTAGGTTACGCACAAGAGTTCCGTAGCT-3'; amplification for 35 cycles of denaturation at 94°C for 30 s, annealing at 60°C for 1 min, and extension at 72°C for 2 min. The cDNA was subcloned into the pCRII vector (Invitrogen) and completely sequenced. The c-Myc cDNA was in vitro translated, and the resulting protein (
Mr 64,000) was easily recognized by anti-c-Myc antibody by Western analysis (not shown). After the generation of Ad-cMyc, expression of c-Myc protein was documented by Western analysis and immunocytochemistry (Fig. 1)
as described below. Ad-E2F-1 was provided by Dr. Joseph R. Nevins (Duke University, Durham, NC). Adenovirus titers and infections were carried out as described previously (33)
.
Western Analysis and Immunocytochemistry.
Protein lysates were prepared, and Western analysis was performed as previously described (32)
, with the following modifications. The Lumigen PS-3 detection reagent (ECL+Plus, Amersham) was used according to the manufacturer’s recommendations. Antihuman c-Myc monoclonal antibody 9E10 clone was obtained from Santa Cruz Biotechnology and the antihuman WAF1 monoclonal antibody Ab1 was obtained from Calbiochem. Immunocytochemistry after adenovirus infection was performed as previously described (34)
.
DNA Synthesis and Apoptosis Assays.
The extent of new DNA synthesis was assessed by [3H]thymidine incorporation assays (25)
and BrdUrd incorporation (35)
as described. DAPI staining of nuclear morphology to evaluate Ad-LacZ- or Ad-cMyc-infected cells for chromosomal DNA fragmentation was carried out as described previously (34)
.
Transfection and Luciferase Assays.
SW480 cells were transfected using human p21-promoter luciferase-reporters and either pCMV-cMyc-S or pCMV-cMyc-AS plasmids, as indicated in the legend to Fig. 4
. The cMyc plasmids drive expression from the human c-Myc cDNA, either in the sense (pCMV-cMyc-S) or antisense (pCMV-cMyc-AS) orientation, driven by the immediate early promoter of CMV. Expression of human c-Myc protein was demonstrated (not shown) after the transfection of NIH3T3 with the sense construct, followed by Western analysis using antihuman c-Myc antibody as described above. Transfections and luci-ferase assays were performed as described previously (36)
. NIH3T3 cells were transfected using the Lipofectamine reagent (Gibco-Bethesda Research Laboratory) as recommended by the manufacturer.
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Footnotes |
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1 K. O. M. is supported by the National Research Service Award Predoctoral Fellowships for Minority Students. W. S. E-D. is an Assistant Investigator of the Howard Hughes Medical Institute. 
2 To whom requests for reprints should be addressed, at Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. Fax: (215) 573-9139; E-mail: weldeir{at}hhmi.upenn.edu
3 The abbreviations used are: TPA, 12-O-tetradecanoylphorbol-13-acetate; MOI, multiplicity of infection; BrdUrd, bromodeoxyuridine; DAPI, 4',6-diamidino-2-phenylindole; Ad, adenovirus.
4 K. O. Mitchell and W. S. El-Deiry, unpublished data.
Received for publication 6/12/98. Revision received 2/ 9/99. Accepted for publication 3/ 3/99.
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References |
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TOPAbstractIntroductionResultsDiscussionMaterials and MethodsReferences |
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in response to growth induction by c-Myc. Proc. Natl. Acad. Sci. USA, 90: 6175-6178, 1993.-prothymosin gene. EMBO J., 10: 133-141, 1991.[Medline]
-gene expression in HIB-1B hibernoma cells through interactions with the core promoter region. Eur. J. Biochem., 232: 397-403, 1995.[Medline]
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G. F. Claassen and S. R. Hann A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor beta -induced cell-cycle arrest PNAS, August 15, 2000; 97(17): 9498 - 9503. [Abstract] [Full Text] [PDF]
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S. Kim, Q. Li, C. V. Dang, and L. A. Lee Induction of ribosomal genes and hepatocyte hypertrophy by adenovirus-mediated expression of c-Myc in vivo PNAS, October 10, 2000; 97(21): 11198 - 11202. [Abstract] [Full Text] [PDF]
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