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Science 18 December 1998:
Vol. 282. no. 5397, pp. 2270 - 2272
DOI: 10.1126/science.282.5397.2270
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Reports

p53-Independent Role of MDM2 in TGF-beta 1 Resistance

Peiqing Sun, Ping Dong, Kang Dai, * Gregory J. Hannon, David Beach dagger

Transforming growth factor-beta (TGF-beta ) inhibits cell proliferation, and acquisition of TGF-beta resistance has been linked to tumorigenesis. A genetic screen was performed to identify complementary DNAs that abrogated TGF-beta sensitivity in mink lung epithelial cells. Ectopic expression of murine double minute 2 rescued TGF-beta -induced growth arrest in a p53-independent manner by interference with retinoblastoma susceptibility gene product (Rb)/E2F function. In human breast tumor cells, increased MDM2 expression levels correlated with TGF-beta resistance. Thus, MDM2 may confer TGF-beta resistance in a subset of tumors and may promote tumorigenesis by interference with two independent tumor suppressors, p53 and Rb.

P. Sun, P. Dong, K. Dai, G. J. Hannon, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA. D. Beach, the Institute of Child Health, 30 Guilford Street, London WC1N, UK.
*   Present address: Chiron Corporation, 4560 Horton Street, Emeryville, CA 94608, USA.

dagger    To whom correspondence should be addressed. E-mail: d.beach{at}ich.ucl.ac.uk

The TGF-beta signaling pathway has been implicated in tumor suppression (1). Loss of TGF-beta sensitivity is frequently observed in tumors derived from cells that are normally sensitive, and the extent of TGF-beta resistance often correlates with malignancy (2). Some tumors may develop TGF-beta resistance following inactivation of essential components of the TGF-beta signaling pathway (3-5) or through deletion of the p15INK4B locus (6). However, such alterations cannot account for the majority of cases in which TGF-beta responsiveness is lost. Therefore, TGF-beta resistance must also be achieved by other mechanisms.

To identify genetic alterations that lead to TGF-beta resistance in tumor cells, we screened for genes that, when overexpressed, allow cells to escape TGF-beta -induced growth arrest (7). A cDNA library was introduced into Mv1Lu, a TGF-beta -sensitive mink lung epithelial cell line, using a retrovirus-based genetic screening system (8). Infected cells were selected for the ability to sustain proliferation in the presence of TGF-beta . We recovered three genes that conferred TGF-beta resistance: Mdm2 c-myc, and NF-IX-1 (Fig. 1, top panel). When treated with TGF-beta , cells expressing MDM2, c-myc, or NF-IX-1 formed colonies and were morphologically identical to untreated cells (Fig. 1) (9). MDM2 also conferred TGF-beta resistance in human mammary epithelial cells (HMECs) (Fig. 1, bottom panel).

Fig. 1. Mdm2, c-myc, and NF-IX-1 bypass TGF-beta -induced growth arrest. (Top panel) Control Mv1Lu or Mv1Lu expressing c-myc, MDM2, or NF-IX-1 (4000 cells) were treated with TGF-beta for 8 days. (Bottom panel) HMECs at passage 14 were infected with a retroviral vector that drives MDM2 expression, and infected cells were selected with hygromycin. After three more passages, HMECs expressing MDM2 or control HMECs (4000 cells) at passage 17 were treated with TGF-beta for 16 days. All cells were visualized by staining with crystal violet. [View Larger Version of this Image (103K GIF file)]

The isolation of c-myc, a gene previously shown to overcome TGF-beta -induced arrest (10), validated the genetic screen. NF-IX-1 is a member of a family of transcription factors that may function in development and differentiation (11). The mechanism by which NF-IX-1 confers TGF-beta resistance remains to be investigated. Because MDM2 is an oncogenic protein that is commonly overexpressed in a broad spectrum of tumors (12), we focused on understanding how this protein confers TGF-beta resistance.

Activation of TGF-beta signaling regulates the expression of a battery of genes. MDM2 overexpression in Mv1Lu cells did not alter the response of known TGF-beta targets (for example, PAI-1, p15, c-myc, and cdc25A) (9), indicating that MDM2 does not confer resistance by disruption of TGF-beta signaling.

MDM2 associates with and inactivates the tumor suppressor protein, p53. To test the possibility that MDM2 bypasses TGF-beta -induced growth arrest through an effect on p53, we investigated whether interference with p53 activity could produce cytokine resistance. Two dominant-negative p53 alleles, p53Val135 (a temperature-sensitive mutant) or p53-175H (13-15) were introduced into Mv1Lu cells, which contain endogenous, wild-type p53 (16). The functionality of these p53-interfering mutants was confirmed by their ability to suppress p53-dependent transcription (9). Cells in which p53 had been inactivated by expression of either dominant-negative mutant retained TGF-beta sensitivity (Fig. 2A). Furthermore, an MDM2 mutant from which the p53-binding domain had been removed failed to bind p53 (Fig. 2C) but still conferred TGF-beta resistance (Fig. 2B). Thus, MDM2 overcomes TGF-beta through a mechanism that is distinct from its ability to inactivate p53.


Fig. 2. MDM2 confers TGF-beta resistance through a p53-independent mechanism in Mv1Lu cells. (A) Control Mv1Lu cells or cells expressing MDM2, p53Val135, or p53-175H were treated with TGF-beta for 8 days. (B) Control Mv1Lu cells or cells expressing MDM2 or an MDM2 mutant that cannot bind p53 were treated with TGF-beta for 8 days. (C) Wild-type or mutant MDM2 proteins were translated in vitro from pcDNA3 in the presence of [35S]methionine and were incubated with a glutathione S-transferase (GST)-p53 fusion protein bound to glutathione-Sepharose 4B beads. Proteins that remained bound to beads after washing (right two lanes) were separated by 12% SDS-polyacrylamide gel electrophoresis, and radiolabeled proteins were visualized by autoradiography. A portion of each in vitro translation reaction is shown for comparison (left two lanes). [View Larger Versions of these Images (105 + 70K GIF file)]

TGF-beta induces G1 arrest through effects on the Rb/E2F pathway (17-19). Because expression of human papillomavirus HPV-16 E7 protein, which abolishes Rb but not p53 function (20), conferred TGF-beta resistance in Mv1Lu cells (9), we investigated the possibility that MDM2 could bypass TGF-beta by interference with the RB/E2F pathway. This hypothesis is consistent with the recent finding that MDM2 can bind directly to Rb and E2F/DP transcription factors (21, 22).

In control Mv1Lu cells, TGF-beta treatment led to a gradual change in Rb phosphorylation status (Fig. 3A). After 24 hours (the time at which growth arrest was established), the majority of Rb had shifted from the hyperphosphorylated form to the growth-inhibitory, hypophosphorylated form. However, in MDM2- and c-myc-expressing cells, the majority of Rb remained in hyperphosphorylated, non-growth-inhibitory state.


Fig. 3. MDM2 overexpression interferes with effects of TGF-beta on the Rb/E2F pathway. (A) Effect of MDM2 on TGF-beta -induced Rb dephosphorylation. Control Mv1Lu cells or cells expressing MDM2 or c-myc were treated with TGF-beta (5 ng/ml) for 0, 2, 12, or 24 hours before lysates were prepared. Protein immunoblots were probed with an antibody against Rb (G3-245, PharMingen), and immunocomplexes were visualized by ECL (Amersham). (B) Effect of MDM2 on the down-regulation of E2F/DP activity by TGF-beta . Control, MDM2-, or c-myc-expressing Mv1Lu cells were transfected with a E2F/DP-dependent luciferase reporter plasmid containing three copies of an E2F/DP DNA binding site (E2FWT-Luc, top panel) or with a non-E2F-dependent luciferase reporter plasmid containing three copies of a mutant E2F DNA binding site (E2FMut-Luc, bottom panel). pSV-LacZ was included as an internal control in all transfections. At 24 hours after transfection, cells were either treated with 5 ng/ml TGF-beta for 18 hours or were left untreated. Luciferase and beta -galactosidase activities were then measured (Promega). Values represent means ±SEM of luciferase activities (normalized to beta -galactosidase activities) from three independent transfections. (C) Effect of MDM2 on the down-regulation of E2F-1. Control, MDM2- or c-myc-expressing Mv1Lu cells were treated with 5 ng/ml TGF-beta for 0, 15, or 27 hours. Cell lysates were prepared, and protein immunoblots were probed with an antibody against E2F-1 (C20, Santa Cruz Biotechnology). [View Larger Versions of these Images (25 + 57 + 39K GIF file)]

E2F proteins are transcription factors that bind to unphosphorylated Rb. Rb phosphorylation releases E2F proteins in an active, growth-promoting form (23). The effect of MDM2 on Rb phosphorylation predicted that MDM2 would have a positive effect on E2F activity. In contrast to previous studies in other cell lines (21, 22), expression of MDM2 in Mv1Lu cells did not increase the activity of an E2F-dependent reporter construct (Fig. 3B). TGF-beta treatment reduced transcription of this reporter by twofold. However, MDM2 expression prevented this reduction (Fig. 3B). Alteration of E2F activity by either TGF-beta treatment or MDM2 overexpression reflected changes in E2F-1 protein levels (Fig. 3C). TGF-beta treatment led to a gradual decrease in E2F-1, and this decrease was prevented by ectopic MDM2 expression. These results indicate that MDM2 rescues TGF-beta -induced growth arrest, at least in part, through maintenance of E2F-1 protein levels and E2F activity. Similar effects were evident in cells that ectopically express c-myc (Fig. 3, B and C), suggesting that c-myc and MDM2 may bypass TGF-beta -induced arrest through overlapping mechanisms.

MDM2 is frequently overexpressed in human tumors (12). We identified one biological consequence of MDM2 overexpression, bypass of TGF-beta -induced growth arrest. TGF-beta induces growth arrest in normal human lymphocytes, melanocytes, and breast epithelial cells. However, cells from human leukemia, lymphomas, melanomas, and breast carcinomas are often TGF-beta resistant (24-27). Coincidentally, MDM2 is commonly overexpressed in these tumors (for example, in 73% of human breast carcinomas) (28-32). Enforced expression of MDM2 in primary HMECs converted these TGF-beta -sensitive cells to a resistant phenotype (Fig. 1, bottom panel). These observations raised the possibility that increased MDM2 expression might contribute to TGF-beta resistance in tumors.

Therefore, we examined the relationship between MDM2 expression levels (Fig. 4A) and TGF-beta responsiveness (Fig. 4B) in seven human breast tumor cell lines. MDM2 was expressed in T-47D, ZR-75-1, and HTB20 cells at levels comparable to those observed in cells (HMEC and Mv1Lu) that had been made TGF-beta -resistant by infection with MDM2 retroviral vectors. These three cell lines were completely resistant to TGF-beta -induced growth arrest. The two cell lines (MCF-7 and BT549) that were most sensitive to TGF-beta treatment had very low MDM2 levels, similar to those seen in TGF-beta -sensitive, normal HMECs. Thus, in several tumor cell lines, increased MDM2 expression strictly correlated with the ability to escape TGF-beta -induced growth inhibition. Two other breast carcinoma cell lines (HBL100 and MDA-MB-468) exhibited partial resistance to TGF-beta despite low levels of MDM2 expression, confirming that other mechanisms (for example, c-myc overexpression, receptor mutation, and so forth) must also contribute to TGF-beta resistance.

Fig. 4. MDM2 expression correlates with resistance to TGF-beta in human breast tumor cell lines. (A) MDM2 protein levels in human breast tumor cell lines. Cell lysates were prepared from the indicated cell lines, and protein immunoblots were probed with an antibody to MDM2 (2A10). (B) TGF-beta responsiveness of human breast tumor cell lines. Human breast tumor cell lines were treated with TGF-beta at the indicated concentrations for 20 days. [View Larger Version of this Image (74K GIF file)]

As breast carcinomas and melanomas become metastatic, they secrete large amounts of TGF-beta (25, 27). This may enhance tumor cell invasion through effects on extracellular matrix (27, 33). Thus, TGF-beta resistance may be an essential adaptation to the metastatic phenotype. In accord with this notion, the extent of TGF-beta resistance correlates with metastatic progression (28, 30), and targeted deletion of an essential component of the TGF-beta signaling cascade, Smad3, promotes the formation of metastatic tumors (1). Although TGF-beta resistance can be achieved through multiple routes, increased expression of MDM2 is sufficient to confer this phenotype.

Previous work indicated that MDM2 may contribute to transformation through mechanisms that are independent of effects on p53. For example, in some human breast carcinomas and lymphomas, p53 mutation and MDM2 overexpression occur together (31, 32). Recently, alternatively spliced forms of MDM2 were identified in bladder and ovarian carcinomas (34). These alternative forms lack the p53-binding domain but still transform NIH-3T3 cells. We have demonstrated that MDM2 can overcome growth inhibition by TGF-beta through effects on the RB/E2F pathway. These results provide a potential mechanism underlying p53-independent oncogenic activities of MDM2. Thus, in tumors, MDM2 may antagonize both the Rb and p53 pathways, functioning in many respects as a cellular version of SV40 large T antigen.

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28 April 1998; accepted 6 November 1998


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   Abstract »    Full Text »    PDF »
MDM2 interacts with the C-terminus of the catalytic subunit of DNA polymerase {varepsilon}.
N. Vlatkovic, S. Guerrera, Y. Li, S. Linn, D. S. Haines, and M. T. Boyd (2000)
Nucleic Acids Res. 28, 3581-3586
   Abstract »    Full Text »    PDF »
The INK4a/ARF locus in murine tumorigenesis.
M. Serrano (2000)
Carcinogenesis 21, 865-869
   Abstract »    Full Text »    PDF »
Regulation of the p53 Tumor Suppressor Protein.
M. Oren (1999)
J. Biol. Chem. 274, 36031-36034
   Full Text »    PDF »
Transforming Growth Factor-{beta} and Breast Cancer Risk in Women With Mammary Epithelial Hyperplasia.
H. Gobbi, W. D. Dupont, J. F. Simpson, W.D. Plummer Jr., P. A. Schuyler, S. J. Olson, C. L. Arteaga, and D. L. Page (1999)
J Natl Cancer Inst 91, 2096-2101
   Abstract »    Full Text »    PDF »
Transforming Growth Factor-beta -mediated p15INK4B Induction and Growth Inhibition in Astrocytes Is SMAD3-dependent and a Pathway Prominently Altered in Human Glioma Cell Lines.
J. N. Rich, M. Zhang, M. B. Datto, D. D. Bigner, and X.-F. Wang (1999)
J. Biol. Chem. 274, 35053-35058
   Abstract »    Full Text »    PDF »
High Expression of MDM2 Protein and Low Rate of p21WAF1/CIP1 Expression in SCID Mice Epstein Barr Virus-induced Lymphoproliferation.
S. El Mansouri, A. Martin, A. Mercadier, C. Capoulade, V. Maréchal, J. Wiels, J. Feuillard, and M. Raphaël (1999)
J. Histochem. Cytochem. 47, 1315-1322
   Abstract »    Full Text »
MDM2 and MDMX Inhibit the Transcriptional Activity of Ectopically Expressed SMAD Proteins.
C. H. Yam, W. Yi Siu, T. Arooz, C. H. S. Chiu, A. Lau, X. Qi Wang, and R. Y. C. Poon (1999)
Cancer Res. 59, 5075-5078
   Abstract »    Full Text »    PDF »
Forward genetics in mammaliancells: functional approaches to gene discovery.
G. R. Stark and AndreiV. Gudkov (1999)
Hum. Mol. Genet. 8, 1925-1938
   Abstract »    Full Text »    PDF »
The E7 Oncoprotein of Human Papillomavirus Type 16 Stabilizes p53 through a Mechanism Independent of p19ARF.
S. E. Seavey, M. Holubar, L. J. Saucedo, and M. E. Perry (1999)
J. Virol. 73, 7590-7598
   Abstract »    Full Text »
Myc Downregulation by Transforming Growth Factor beta Required for Activation of the p15Ink4b G1 Arrest Pathway.
B. J. Warner, S. W. Blain, J. Seoane, and J. Massague (1999)
Mol. Cell. Biol. 19, 5913-5922
   Abstract »    Full Text »    PDF »
twist is a potential oncogene that inhibits apoptosis.
R. Maestro, A. P. D. Tos, Y. Hamamori, S. Krasnokutsky, V. Sartorelli, L. Kedes, C. Doglioni, D. H. Beach, and G. J. Hannon (1999)
Genes & Dev. 13, 2207-2217
   Abstract »    Full Text »
Functional Approaches to Gene Isolation in Mammalian Cells.
A. V. Gudkov, I. B. Roninson, R. Brown;, A. Kimchi, O. Cohen, J. Kissil, T. Raveh, B. Inbal, N. Levy-Strumpf, H. Berissi, et al. (1999)
Science 285, 299a-299
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The Pathway Regulating MDM2 Protein Degradation Can Be Altered in Human Leukemic Cells.
Y. Pan and D. S. Haines (1999)
Cancer Res. 59, 2064-2067
   Abstract »    Full Text »    PDF »
Stabilization of the MDM2 Oncoprotein by Mutant p53.
Y. Peng, L. Chen, C. Li, W. Lu, S. Agrawal, and J. Chen (2001)
J. Biol. Chem. 276, 6874-6878
   Abstract »    Full Text »    PDF »
A Novel Cellular Protein (MTBP) Binds to MDM2 and Induces a G1 Arrest That Is Suppressed by MDM2.
M. T. Boyd, N. Vlatkovic, and D. S. Haines (2000)
J. Biol. Chem. 275, 31883-31890
   Abstract »    Full Text »    PDF »
Mullerian Inhibiting Substance Inhibits Ovarian Cell Growth through an Rb-independent Mechanism.
T. U. Ha, D. L. Segev, D. Barbie, P. T. Masiakos, T. T. Tran, D. Dombkowski, M. Glander, T. R. Clarke, H. K. Lorenzo, P. K. Donahoe, et al. (2000)
J. Biol. Chem. 275, 37101-37109
   Abstract »    Full Text »    PDF »
Different Sensitivity of the Transforming Growth Factor-beta Cell Cycle Arrest Pathway to c-Myc and MDM-2.
S. W. Blain and J. Massague (2000)
J. Biol. Chem. 275, 32066-32070
   Abstract »    Full Text »    PDF »
Cyclin A-CDK Phosphorylation Regulates MDM2 Protein Interactions.
T. Zhang and C. Prives (2001)
J. Biol. Chem. 276, 29702-29710
   Abstract »    Full Text »    PDF »


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Science. ISSN 0036-8075 (print), 1095-9203 (online)