Mutant P53-induced Up-regulation of Mitogen-activated Protein Kinase Kinase 3 Contributes to Gain of Function

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Mar 13

PMID 20223820

Citations 54

Authors

Aymone Gurtner

Giuseppe Starace

Giuseppe Norelli

Giulia Piaggio

Ada Sacchi

Gianluca Bossi

Affiliations

Soon will be listed here.

Abstract

Mitogen-activated protein kinase kinase 3 (MAP2K3) is a member of the dual specificity kinase group. Growing evidence links MAP2K3 to invasion and tumor progression. Here, we identify MAP2K3 as a transcriptional target of endogenous gain-of-function p53 mutants R273H, R175H, and R280K. We show that MAP2K3 modulation occurred at the mRNA and protein levels and that endogenous mutant p53 proteins are capable of binding to and activate the MAP2K3 promoter. In addition, we found that the studied p53 mutants regulate MAP2K3 gene expression through the involvement of the transcriptional cofactors NF-Y and NF-kappaB. Finally, functional studies showed that endogenous MAP2K3 knockdown inhibits proliferation and survival of human tumor cells, whereas the ectopic expression of MAP2K3 can rescue the proliferative defect induced by mutant p53 knockdown. Taken together, our findings define a novel player through which mutant p53 exerts its gain-of-function activity in cancer cells.

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References

Brazdova M, Quante T, Togel L, Walter K, Loscher C, Tichy V . Modulation of gene expression in U251 glioblastoma cells by binding of mutant p53 R273H to intronic and intergenic sequences. Nucleic Acids Res. 2009; 37(5):1486-500. PMC: 2655687. DOI: 10.1093/nar/gkn1085. View

Notterman D, Alon U, Sierk A, Levine A . Transcriptional gene expression profiles of colorectal adenoma, adenocarcinoma, and normal tissue examined by oligonucleotide arrays. Cancer Res. 2001; 61(7):3124-30. View

Mizuarai S, Yamanaka K, Kotani H . Mutant p53 induces the GEF-H1 oncogene, a guanine nucleotide exchange factor-H1 for RhoA, resulting in accelerated cell proliferation in tumor cells. Cancer Res. 2006; 66(12):6319-26. DOI: 10.1158/0008-5472.CAN-05-4629. View

Weisz L, Zalcenstein A, Stambolsky P, Cohen Y, Goldfinger N, Oren M . Transactivation of the EGR1 gene contributes to mutant p53 gain of function. Cancer Res. 2004; 64(22):8318-27. DOI: 10.1158/0008-5472.CAN-04-1145. View

Aas T, Borresen A, Geisler S, Smith-Sorensen B, Johnsen H, Varhaug J . Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med. 1996; 2(7):811-4. DOI: 10.1038/nm0796-811. View

Matas D, Sigal A, Stambolsky P, Milyavsky M, Weisz L, Schwartz D . Integrity of the N-terminal transcription domain of p53 is required for mutant p53 interference with drug-induced apoptosis. EMBO J. 2001; 20(15):4163-72. PMC: 149170. DOI: 10.1093/emboj/20.15.4163. View

Olson A, Sheth N, Lee J, Hannon G, Sachidanandam R . RNAi Codex: a portal/database for short-hairpin RNA (shRNA) gene-silencing constructs. Nucleic Acids Res. 2005; 34(Database issue):D153-7. PMC: 1347414. DOI: 10.1093/nar/gkj051. View

Mantovani R . A survey of 178 NF-Y binding CCAAT boxes. Nucleic Acids Res. 1998; 26(5):1135-43. PMC: 147377. DOI: 10.1093/nar/26.5.1135. View

Bossi G, Marampon F, Maor-Aloni R, Zani B, Rotter V, Oren M . Conditional RNA interference in vivo to study mutant p53 oncogenic gain of function on tumor malignancy. Cell Cycle. 2008; 7(12):1870-9. DOI: 10.4161/cc.7.12.6161. View

10.

Gilmore T, Herscovitch M . Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene. 2006; 25(51):6887-99. DOI: 10.1038/sj.onc.1209982. View

11.

Kozma S, Bogaard M, Buser K, Saurer S, Bos J, Groner B . The human c-Kirsten ras gene is activated by a novel mutation in codon 13 in the breast carcinoma cell line MDA-MB231. Nucleic Acids Res. 1987; 15(15):5963-71. PMC: 306061. DOI: 10.1093/nar/15.15.5963. View

12.

Derijard B, Raingeaud J, Barrett T, Wu I, Han J, Ulevitch R . Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995; 267(5198):682-5. DOI: 10.1126/science.7839144. View

13.

Rhodes D, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D . ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004; 6(1):1-6. PMC: 1635162. DOI: 10.1016/s1476-5586(04)80047-2. View

14.

Bullock A, Fersht A . Rescuing the function of mutant p53. Nat Rev Cancer. 2002; 1(1):68-76. DOI: 10.1038/35094077. View

15.

Kim E, Deppert W . Transcriptional activities of mutant p53: when mutations are more than a loss. J Cell Biochem. 2004; 93(5):878-86. DOI: 10.1002/jcb.20271. View

16.

Bossi G, Lapi E, Strano S, Rinaldo C, Blandino G, Sacchi A . Mutant p53 gain of function: reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression. Oncogene. 2005; 25(2):304-9. DOI: 10.1038/sj.onc.1209026. View

17.

Miller L, Smeds J, George J, Vega V, Vergara L, Ploner A . An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci U S A. 2005; 102(38):13550-5. PMC: 1197273. DOI: 10.1073/pnas.0506230102. View

18.

Weisz L, Oren M, Rotter V . Transcription regulation by mutant p53. Oncogene. 2007; 26(15):2202-11. DOI: 10.1038/sj.onc.1210294. View

19.

Wiznerowicz M, Trono D . Conditional suppression of cellular genes: lentivirus vector-mediated drug-inducible RNA interference. J Virol. 2003; 77(16):8957-61. PMC: 167245. DOI: 10.1128/jvi.77.16.8957-8951.2003. View

20.

Lin J, Teresky A, Levine A . Two critical hydrophobic amino acids in the N-terminal domain of the p53 protein are required for the gain of function phenotypes of human p53 mutants. Oncogene. 1995; 10(12):2387-90. View