PT  - JOURNAL ARTICLE
AU  - Siddharth Singh
AU  - Manoj Kumar
AU  - Sanjeev Kumar
AU  - Shrinka Sen
AU  - Pawan Upadhyay
AU  - M Naveen
AU  - Vivek S. Tomar
AU  - Amit Dutt
AU  - Tapas K. Kundu
TI  - Activation of Multiple Signalling Pathways by P152Lp53 Mutant Reveals New Gain-of-function Implicating Tumorigenesis
AID  - 10.1101/475293
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 475293
4099  - http://biorxiv.org/content/early/2018/11/20/475293.short
4100  - http://biorxiv.org/content/early/2018/11/20/475293.full
AB  - TP53 is the most frequently mutated tumor suppressor gene in context of all varieties of cancer, yet biochemical characterization of several reported mutations with probable biological significance have not been accomplished. We have identified a relatively rare proline to leucine mutation (P152L) in p53 in an Indian oral cancer patient sample at the fade end of its DNA binding domain (DBD). Although P152Lp53 DBD potentially binds to DNA, the full length protein is completely devoid of DNA binding ability at its cognate site. Interestingly, P152Lp53 can efficiently tetramerize. Significantly, this mutant when expressed in p53 null cell line, was found to induce cell mobility, proliferation, and invasion as compared to vector control. Also, enhanced tumorigenic potential was observed when cells expressing P152Lp53 were xenografted into nude mice, the mechanistic details of which were also investigated upon where several of the pathways were found to be upregulated such as Cell-Cell/Cell-ECM signalling, EGFR signalling, Rho-GTPase signalling. Taken together, this study establishes P152Lp53 as a new gain of function mutant.