RT Journal Article
SR Electronic
T1 Activation of Multiple Signalling Pathways by P152Lp53 Mutant Reveals New Gain-of-function Implicating Tumorigenesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 475293
DO 10.1101/475293
A1 Siddharth Singh
A1 Manoj Kumar
A1 Sanjeev Kumar
A1 Shrinka Sen
A1 Pawan Upadhyay
A1 M Naveen
A1 Vivek S. Tomar
A1 Amit Dutt
A1 Tapas K. Kundu
YR 2018
UL http://biorxiv.org/content/early/2018/11/20/475293.abstract
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.