Upregulation of the Mitochondrial Transport Protein, Tim50, by Mutant P53 Contributes to Cell Growth and Chemoresistance

The p53 gene is one of the most frequently mutated genes in human cancer. Some p53 mutations impart additional functions that promote oncogenesis. To investigate how these p53 mutants function, a proteomic analysis was performed. The protein, translocator of the inner mitochondrial membrane 50 (Tim50), was upregulated in a non-small cell lung carcinoma cell line (H1299) that expressed the p53 mutants R175H and R273H compared to cells lacking p53. Tim50 was also elevated in the breast cancer cell lines MDA-MB-468 and SK-BR-3, that endogenously express the p53 mutants R175H and R273H, respectively, compared to MCF-10A. The p53 mutants R175H and R273H, but not WT p53, upregulated the expression of a Tim50 promoter construct and chromatin immunoprecipitation (ChIP) analysis indicated increased histone acetylation and increased interaction of the transcription factors Ets-1, CREB and CREB-binding protein (CBP) with the Tim50 promoter in the presence of mutant p53. Finally, reduction of Tim50 expression reduced the growth rate and chemoresistance of cells harboring mutant p53 but had no effect upon cells lacking p53. Taken together, these findings identify the Tim50 gene as a transcriptional target of mutant p53 and suggest a novel mechanism by which p53 mutants enhance cell growth and chemoresistance.