A Role for Transcriptional Repression of P21CIP1 by C-Myc in Overcoming Transforming Growth Factor Beta -induced Cell-cycle Arrest

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2000 Aug 2

PMID 10920185

Citations 83

Authors

G F Claassen

S R Hann

Affiliations

Soon will be listed here.

Abstract

c-Myc plays a vital role in cell-cycle progression. Deregulated expression of c-Myc can overcome cell-cycle arrest in order to promote cellular proliferation. Transforming growth factor beta (TGFbeta) treatment of immortalized human keratinocyte cells inhibits cell-cycle progression and is characterized by down-regulation of c-Myc followed by up-regulation of p21(CIP1). A direct role of c-Myc in this pathway was demonstrated by the observation that ectopic expression of c-Myc overcame the cell-cycle block induced by TGFbeta treatment. The induction of p21(CIP1) transcription by TGFbeta was blocked in human keratinocyte cells stably expressing c-Myc. Furthermore, overexpression of c-Myc in NIH 3T3 cells repressed the basal levels of p21(CIP1) mRNA. Repression of p21(CIP1) transcription by c-Myc occurred at the promoter level in a region near the start site of transcriptional initiation and was independent of histone deacetylase activity. These data suggest that the down-regulation of c-Myc after TGFbeta signaling is important for subsequent regulation of p21(CIP1) and cell-cycle inhibition. Thus, repression of the cell-cycle inhibitory gene p21(CIP1) plays a role in c-Myc-dependent cell-cycle progression.

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References

Timchenko N, Wilde M, Nakanishi M, Smith J, Darlington G . CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein. Genes Dev. 1996; 10(7):804-15. DOI: 10.1101/gad.10.7.804. View

Gartel A, Tyner A . Transcriptional regulation of the p21((WAF1/CIP1)) gene. Exp Cell Res. 1999; 246(2):280-9. DOI: 10.1006/excr.1998.4319. View

Borre A, Cultraro C, Segal S . c-Myc inactivation by mutant Max alters growth and morphology of NCI-H-630 colon cancer cells. J Cell Physiol. 1996; 169(1):200-8. DOI: 10.1002/(SICI)1097-4652(199610)169:1<200::AID-JCP20>3.0.CO;2-F. View

Malliri A, Yeudall W, Nikolic M, Crouch D, Parkinson E, Ozanne B . Sensitivity to transforming growth factor beta 1-induced growth arrest is common in human squamous cell carcinoma cell lines: c-MYC down-regulation and p21waf1 induction are important early events. Cell Growth Differ. 1996; 7(10):1291-304. View

Longstreet M, Miller B, Howe P . Loss of transforming growth factor beta 1 (TGF-beta 1)-induced growth arrest and p34cdc2 regulation in ras-transfected epithelial cells. Oncogene. 1992; 7(8):1549-56. View

Billon N, van Grunsven L, Rudkin B . The CDK inhibitor p21WAF1/Cip1 is induced through a p300-dependent mechanism during NGF-mediated neuronal differentiation of PC12 cells. Oncogene. 1996; 13(10):2047-54. View

Coller H, Grandori C, Tamayo P, Colbert T, Lander E, Eisenman R . Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc Natl Acad Sci U S A. 2000; 97(7):3260-5. PMC: 16226. DOI: 10.1073/pnas.97.7.3260. View

Hann S, Abrams H, Rohrschneider L, Eisenman R . Proteins encoded by v-myc and c-myc oncogenes: identification and localization in acute leukemia virus transformants and bursal lymphoma cell lines. Cell. 1983; 34(3):789-98. DOI: 10.1016/0092-8674(83)90535-4. View

Coffey Jr R, Bascom C, Sipes N, Weissman B, Moses H . Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta. Mol Cell Biol. 1988; 8(8):3088-93. PMC: 363535. DOI: 10.1128/mcb.8.8.3088-3093.1988. View

10.

Karn J, Watson J, Lowe A, Green S, Vedeckis W . Regulation of cell cycle duration by c-myc levels. Oncogene. 1989; 4(6):773-87. View

11.

Pietenpol J, Holt J, Stein R, Moses H . Transforming growth factor beta 1 suppression of c-myc gene transcription: role in inhibition of keratinocyte proliferation. Proc Natl Acad Sci U S A. 1990; 87(10):3758-62. PMC: 53982. DOI: 10.1073/pnas.87.10.3758. View

12.

Spotts G, Hann S . Enhanced translation and increased turnover of c-myc proteins occur during differentiation of murine erythroleukemia cells. Mol Cell Biol. 1990; 10(8):3952-64. PMC: 360906. DOI: 10.1128/mcb.10.8.3952-3964.1990. View

13.

Eilers M, Schirm S, Bishop J . The MYC protein activates transcription of the alpha-prothymosin gene. EMBO J. 1991; 10(1):133-41. PMC: 452621. DOI: 10.1002/j.1460-2075.1991.tb07929.x. View

14.

Landesman Y, Pagano M, Draetta G, Rotter V, Fusenig N, Kimchi A . Modifications of cell cycle controlling nuclear proteins by transforming growth factor beta in the HaCaT keratinocyte cell line. Oncogene. 1992; 7(8):1661-5. View

15.

Roy A, Carruthers C, Gutjahr T, Roeder R . Direct role for Myc in transcription initiation mediated by interactions with TFII-I. Nature. 1993; 365(6444):359-61. DOI: 10.1038/365359a0. View

16.

Hateboer G, Timmers H, Rustgi A, Billaud M, van t Veer L, Bernards R . TATA-binding protein and the retinoblastoma gene product bind to overlapping epitopes on c-Myc and adenovirus E1A protein. Proc Natl Acad Sci U S A. 1993; 90(18):8489-93. PMC: 47382. DOI: 10.1073/pnas.90.18.8489. View

17.

El-Deiry W, Tokino T, Velculescu V, Levy D, Parsons R, Trent J . WAF1, a potential mediator of p53 tumor suppression. Cell. 1993; 75(4):817-25. DOI: 10.1016/0092-8674(93)90500-p. View

18.

Maheswaran S, Lee H, Sonenshein G . Intracellular association of the protein product of the c-myc oncogene with the TATA-binding protein. Mol Cell Biol. 1994; 14(2):1147-52. PMC: 358470. DOI: 10.1128/mcb.14.2.1147-1152.1994. View

19.

Gaire M, Magbanua Z, McDonnell S, McNeil L, Lovett D, Matrisian L . Structure and expression of the human gene for the matrix metalloproteinase matrilysin. J Biol Chem. 1994; 269(3):2032-40. View

20.

Noda A, Ning Y, Venable S, Smith J . Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res. 1994; 211(1):90-8. DOI: 10.1006/excr.1994.1063. View