Abstract
Cytokine oncostatin M (OM) exerts growth-inhibitory and differentiative effects on breast cancer cells. Previously we showed that the transcription from the p53 gene in breast cancer cells was down regulated by OM. To elucidate the molecular mechanisms underlying the OM effect on p53 transcription, in this study, we dissected the p53 promoter region and analysed the p53 promoter activity in breast tumor cells. We showed that treatment of MCF-7 cells with OM induced a dose- and time-dependent suppression of p53 promoter activity. The p53 promoter activity was decreased to 35% of control at 24 h and further decreased to 20% at 48 h by OM at concentrations of 5 ng/ml and higher. Deletion of the 5′-flanking region of the p53 promoter from −426 to −97 did not affect the OM effect. However, further deletion to −40 completely abolished the repressive effect of OM. The p53 promoter region −96 to −41 contains NF-κB and c-myc binding sites, and a newly identified UV-inducible element PE21. Mutations to disrupt NF-κB binding or c-myc binding to the p53 promoter decreased the basal promoter activity without affecting the OM-mediated suppression, whereas mutation at the PE21 motif totally abolished the OM effect. We further demonstrated that insertion of PE21 element upstream of the thymidine kinase minimal promoter generated an OM response analogous to that of the p53 promoter. Finally, we detected the specific binding of a nuclear protein with a molecular mass of 87 kDa to the PE21 motif. Taken together, we demonstrate that OM inhibits the transcription of the p53 gene through the PE21 element. Thus, the PE21 element is functionally involved in p53 transcription regulated by UV-induction and OM suppression.
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Abbreviations
- EMSA:
-
electrophoretic mobility shift assay
- FBS:
-
fetal bovine serum
- LIF:
-
leukemia inhibitory factor
- OM:
-
oncostatin M
- TK:
-
thymidine kinase
References
Balint E, Reisman D . 1996 Cancer Research 56: 1648–1653
Benoit V, Hellin A, Huygen S, Gielen J, Bours V, Merville M . 2000 Oncogene 19: 4787–4794
Briggs J, Kudlow J, Kraft A . 1996 J. Biol. Chem. 271: 901–906
Datto M, Yu Y, Wang X . 1995 J. Biol. Chem. 270: 28623–28628
Douglas A, Goss A, Sutherland R, Hilton D, Berndt M, Nicola N, Begley C . 1997 Oncogene 14: 661–669
Douglas A, Grant S, Goss G, Clouston D, Sutherland R, Begley C . 1998 Int. J. Cancer 75: 64–73
Estrov Z, Samal B, Kellokumpulehtinen P, Sahin AA, Kurzrock R, Talpaz M, Aggarwal BB . 1995 J. Interferon Cytokine Res. 15: 905–913
Hirose Y, Berger M, Pieper R . 2001 Cancer Research 61: 1957–1963
Horn D, Fitzpatrick W, Gompper P, Ochs V, Bolton-Hanson M, Zarling J, Malik N, Todaro G, Linsley P . 1990 Growth Factors 2: 157–165
Huang L, Sowa Y, Sakai T, Bpardee A . 2000 Oncogene 19: 5712–5719
Ito A, Lai C, Zhao X, Saito S, Hamilton M, Appella E, Yao T . 2001 EMBO J. 20: 1331–1340
Jeffy B, Chen E, Gudas J, Romagnolo D . 2000 Neoplasia 2: 460–470
Kao S, Lemoine F, Marriott S . 2000 J. Biol. Chem. 275: 35926–35931
Kirch H-C, Flaswinkel S, Rumpf H, Brockmann D, Esche H . 1999 Oncogene 18: 2728–2738
Lee M, Song H, Park S, Park J . 1998 Biol. Chem. 379: 1333–1340
Lee M, Song H, Yu S, Lee K, Park J . 1999 Biochem. Cell. Biol. 77: 209–214
Lee S, Rho H . 2000 Oncogene 19: 468–471
Liu J, Spence M, Wallace P, Forcier K, Hellstrom I, Vestal R . 1997 Cell. Growth Differ. 8: 667–676
Liu J, Li C, Ahlborn T, Spence M, Meng L, Boxer L . 1999 Cell. Growth Differ. 5: 15–18
Liu J, Ahlborn T, Briggs M, Kraemer F . 2000 J. Biol. Chem. 275: 5214–5221
Mokdad-Gargouri R, Belhadj K, Gargouri A . 2001 Nucleic Acids Res. 29: 1222–1227
Nakano K, Balint E, Ashcroft M, Vousden K . 2000 Oncogene 19: 4283–4289
Nakano K, Mizuno T, Sowa Y, Orita T, Okuyama Y, Fujita T, Ohtani F, Matsukawa Y, Tokino T . 1997 J. Biol. Chem. 272: 22199–22206
Nayak B, Das B . 1999 Mol. Biol. Rep. 26: 223–230
Noda A, Toma-Aiba Y, Fujiwaba Y . 2000 Oncogene 19: 21–31
Phan SC, Feeley B, Withers D, Boxer LM . 1996 Mol. Cell. Biol. 16: 2387–2393
Peeper D, Dannenberg J, Riele H, Bernards R . 2001 Nat. Cell. Biol. 3: 198–203
Pei X, Nakanish Y, Takayama K, Bai F, Hara N . 1999 J. Biol. Chem. 274: 35240–35246
Raman V, Martensaen S, Reisman D, Evron E, Odenwald W, Faffee M, Sukumar S . 2000 Nature 405: 974–978
Reich N, Levine A . 1984 Nature 308: 199–201
Seluanov A, Gorbunova V, Falcovitz A, Sigal A, Milyavsky M, Zurer I, Shohat G, Goldfinger N . 2001 Mol. Cell. Biol. 21: 1552–1564
Soini Y, Kamel D, Nuorva K, Lane D, Vahakangsa K . 1992 Pathol. Anat. Histopathol. 421: 415–420
Sowa Y, Orita T, Minamikawa S, Nakano K, Mizuno T, Normura H, Sakai T . 1997 Biochem. Biophys. Res. Comm. 241: 142–150
Spence M, Vestal R, Liu J . 1997 Cancer Research 57: 2223–2228
Stuart E, Haffner R, Oren M, Gruss P . 1995 EMBO J. 14: 5638–5645
Tuck S, Craword L . 1989 Mol. Cell. Biol. 9: 2163–2172
Uberti D, Grilli M . 2000 Amino Acids 19: 253–261
Wang J, Friedman E . 2000 Mol. Carcinog. 29: 179–188
Wang X, Ongkeko W, Lau A, Leung K, Poon R . 2001 Cancer Research 61: 1598–1603
Xu D, Wang Q, Gruber A, Bjorkholm M, Chen Z, Zaid A, Selivanova G, Peterson C, Wiman K, Pisa P . 2000 Oncogene 19: 5123–5133
Zarling J, Shoyab M, Marquardt H, Hanson M, Lionbin M, Todaro G . 1986 Proc. Natl. Acad. Sci. USA 83: 9739–9743
Zeng X, Keller D, Wu L, Lu H . 2000 Cancer Research 60: 6184–6188
Zhu Q, Wani M, El-Mahdy M, Wani G, Wanni A . 2000 Mol. Carcinog. 28: 215–224
Acknowledgements
This study was supported by the Department of Veterans Affairs (Office of Research and Development, Medical Research Service), by grant (1RO1CA83648-01) from National Cancer Institute, and by grant (BC990960) from the United States Army Medical Research and Development Command.
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Li, C., Ahlborn, T., Tokita, K. et al. The critical role of the PE21 element in oncostatin M-mediated transcriptional repression of the p53 tumor suppressor gene in breast cancer cells. Oncogene 20, 8193–8202 (2001). https://doi.org/10.1038/sj.onc.1205046
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DOI: https://doi.org/10.1038/sj.onc.1205046
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