p73 shares substantial structural and functional homology with p53. p73 can integrate diverse incoming death signals in vivo including DNA damage, oncogene deregulation and activation of T cell receptors, and in response mediate apoptosis in primary and tumor cells. For example, we recently showed that endogenous p73 is induced and activated by the oncogenes E2F1, cMyc and EtA. Nevertheless, p73's precise role in tumorigenesis is unclear because current genetic and expression data do not support a classic Knudson-type suppressor role. The mouse p73 gene is regulated by two promoters P1 and P2, with P1 producing full length p73 and P2 producing dominant negative deltaNp73 that lacks the transactivation domain. In mouse, deltaNp73 plays an important anti-apoptotic role in counteracting p53-mediated neuronal death during the sculpting of the developing brain. We have evidence that human p73 also has a functional P2 promoter which is generating deltaNp73 transcripts in tumors. Here we hypothesize that human p73 has an anti-tumor safeguard role in vivo, albeit weaker than p53, which is epigenetically rather than genetically targeted in tumors. We further hypothesize that a main mechanism of epigenetic p73 targeting is mediated through dominant negative interactions between p73 and i) mutant p53 proteins in tumors with p53 mutations ('double hit') and ii) transactivation-deficient isoforms of p73 itself such as deltaNp73. This epigenetic model could explain i) the lack of p73 mutations in human cancer, ii) the frequent tumor-associated overexpression of the p73 gene, since the contribution by dominant negative isoforms is currently not known and iii) the failure of p73-deficient mice to develop spontaneous tumors, because the presence of p53 could substitute for the suppressor function of p73. We will test this notion using genetic, functional and biochemical approaches in human tumors, cells lines and by generating an inducible deltaNp73 transgenic mouse model. We will also explore whether other established human oncogenes can activate p73.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093853-04
Application #
6921975
Study Section
Special Emphasis Panel (ZRG1-PTHC (01))
Program Officer
Blair, Donald G
Project Start
2002-01-14
Project End
2006-12-31
Budget Start
2005-01-13
Budget End
2005-12-31
Support Year
4
Fiscal Year
2005
Total Cost
$301,376
Indirect Cost
Name
State University New York Stony Brook
Department
Pathology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Holembowski, Lena; Kramer, Daniela; Riedel, Dietmar et al. (2014) TAp73 is essential for germ cell adhesion and maturation in testis. J Cell Biol 204:1173-90
Yallowitz, A R; Alexandrova, E M; Talos, F et al. (2014) p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis. Cell Death Differ 21:645-54
Alexandrova, E M; Talos, F; Moll, U M (2013) p73 is dispensable for commitment to neural stem cell fate, but is essential for neural stem cell maintenance and for blocking premature differentiation. Cell Death Differ 20:368
Alexandrova, E M; Petrenko, O; Nemajerova, A et al. (2013) ?Np63 regulates select routes of reprogramming via multiple mechanisms. Cell Death Differ 20:1698-708
Hofstetter, Gerda; Berger, Astrid; Berger, Regina et al. (2012) The N-terminally truncated p53 isoform ?40p53 influences prognosis in mucinous ovarian cancer. Int J Gynecol Cancer 22:372-9
Vaseva, A V; Yallowitz, A R; Marchenko, N D et al. (2011) Blockade of Hsp90 by 17AAG antagonizes MDMX and synergizes with Nutlin to induce p53-mediated apoptosis in solid tumors. Cell Death Dis 2:e156
Li, D; Marchenko, N D; Moll, U M (2011) SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis. Cell Death Differ 18:1904-13
Beyer, Ulrike; Moll-Rocek, Julian; Moll, Ute M et al. (2011) Endogenous retrovirus drives hitherto unknown proapoptotic p63 isoforms in the male germ line of humans and great apes. Proc Natl Acad Sci U S A 108:3624-9
Li, Dun; Marchenko, Natalia D; Schulz, Ramona et al. (2011) Functional inactivation of endogenous MDM2 and CHIP by HSP90 causes aberrant stabilization of mutant p53 in human cancer cells. Mol Cancer Res 9:577-88
Holembowski, Lena; Schulz, Ramona; Talos, Flaminia et al. (2011) While p73 is essential, p63 is completely dispensable for the development of the central nervous system. Cell Cycle 10:680-9

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