The short-term objectives of this study are to test the following hypotheses: 1) Expression of certain p53 mutants in human mammary epithelial cells (hMEC) results in mutant p53-mediated transactivation of genes involved in oncogenesis, such as those needed for cell survival and angiogenesis. This """"""""gain of function"""""""" of mutant p53 contributes to one of the steps of oncogenesis. 2) """"""""Gain of function"""""""" can be partially explained by mutant p53's interaction with and consequent inactivation of p53-homologue p73 and p63, as evident by changes in the expression profile of genes regulated by p73 and p63. 3)""""""""Gain of function""""""""/""""""""dominant negative"""""""" phenotype of mutant p53 can be partially attributed to the change in the expression profile of genes modulated by wild-type p53 in the presence of mutant p53. We observed that mutant p53-281G induces in vivo expression of a number of genes involved in cell survival, and angiogenesis, including Integrin a and sphingosine kinase I, an antiapoptotic gene product. Integrins strongly influence metastatic potential of some breast cancers. We and others have observed that breast cancer-derived p53 mutants interfere with functions of p73 and wild-type p53, presumably by physically interacting with them. The following are the specific aims:
Specific Aim 1 : To identify genes specifically modulated by tumor-derived p53 mutants in mammary epithelial cells (MEC) through transactivation or transrepression.
Specific Aim 2 : To identify a possible mechanism of transactivation and transrepression used by mutant derived p53.
Specific Aim 3 : To determine the consequences in gene expression induced by p73 and wild-type p53 in cells harboring p53-mutations.
| Scian, M J; Carchman, E H; Mohanraj, L et al. (2008) Wild-type p53 and p73 negatively regulate expression of proliferation related genes. Oncogene 27:2583-93 |
| Scian, Mariano J; Stagliano, Katherine E R; Anderson, Michelle A E et al. (2005) Tumor-derived p53 mutants induce NF-kappaB2 gene expression. Mol Cell Biol 25:10097-110 |
| Scian, Mariano J; Stagliano, Katherine E R; Ellis, Michelle A et al. (2004) Modulation of gene expression by tumor-derived p53 mutants. Cancer Res 64:7447-54 |
| Scian, Mariano J; Stagliano, Katherine E R; Deb, Debabrita et al. (2004) Tumor-derived p53 mutants induce oncogenesis by transactivating growth-promoting genes. Oncogene 23:4430-43 |
