The major mechanism for the inactivation of the p53 tumor suppressor gene is missense mutations, which consequently result in the production of a mutant protein with the ability to promote cancer. Although mutant p53 can interfere with the function of wildtype p53, the majority of human cancers that express mutant p53 have lost wildtype p53. There are at least two major mechanisms through which the mutant p53 protein functions as an oncogene: the first involves the physical inactivation of other tumor suppressor proteins such as its family members, p63 and p73, and the other is dependent on its ability to regulate gene expression. There is a paucity of data that provide a mechanistic explanation of how mutant p53 regulates specific gene targets that play key roles in human cancer. Given the high frequency of p53 mutations and the established role of mutant p53 in promoting cancer development, a detailed understanding of this oncogene's transcriptional regulatory activity may open novel opportunities for targeted inactivation of its carcinogenesis promoting activities. The overarching hypothesis of this proposal is that mutant p53 cooperates with other transcription factors to regulate genes involved in cell growth, survival and chemotherapy resistance. The research plan will provide a detailed analysis of the formation of a transcriptional regulatory complex involving mutant p53 and ETS2, a characterization of the sequence specific binding activity of this transcription factor complex, and the contribution of this complex to mutant p53's oncogenic function. The three specific aims are:
Specific Aim 1 : Determine the role of ETS2 in mutant p53's regulation of transcription.
Specific Aim 2 : Determine the role of mutant p53 and ETS complexes in the regulation of senescence and aberrant Ras signaling.
Specific Aim 3 : Identification of liabilities in the mutant p53 transcriptome.
One of the most frequently occurring genetic lesions in human cancers is the mutation of the p53 tumor suppressor gene. The results from this work will define how the mutant p53 promotes the development of cancer and the acquisition of chemotherapy resistance.
|Martinez, Luis Alfonso (2016) Mutant p53 and ETS2, a Tale of Reciprocity. Front Oncol 6:35|
|Carrero, Zunamys I; Kollareddy, Madhusudhan; Chauhan, Krishna M et al. (2016) Mutant p53 protects ETS2 from non-canonical COP1/DET1 dependent degradation. Oncotarget 7:12554-67|
|Chauhan, Krishna M; Ramakrishnan, Gopalakrishnan; Kollareddy, Madhusudhan et al. (2016) Characterization of cancer-associated missense mutations in MDM2. Mol Cell Oncol 3:e1125986|
|Kollareddy, Madhusudhan; Dimitrova, Elizabeth; Vallabhaneni, Krishna C et al. (2015) Regulation of nucleotide metabolism by mutant p53 contributes to its gain-of-function activities. Nat Commun 6:7389|