The cancer-associated, gain-of-function TP53 variant P152Lp53 activates multiple signaling pathways implicated in tumorigenesis

Singh, Siddharth and Kumar, Manoj and Kumar, Sanjeev and Sen, Shrinka and Upadhyay, Pawan and Bhattacharjee, Sayan and Naveen, M and Tomar, Vivek Singh and Roy, Siddhartha and Dutt, Amit and Kundu, Tapas K (2019) The cancer-associated, gain-of-function TP53 variant P152Lp53 activates multiple signaling pathways implicated in tumorigenesis. In: JOURNAL OF BIOLOGICAL CHEMISTRY, 294 (38). pp. 14081-14095.

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Abstract

TP53 is the most frequently mutated tumor suppressor gene in many cancers, yet biochemical characterization of several of its reported mutations with probable biological significance have not been accomplished enough. Specifically, missense mutations in TP53 can contribute to tumorigenesis through gain-of-function of biochemical and biological properties that stimulate tumor growth. Here, we identified a relatively rare mutation leading to a proline to leucine substitution (P152L) in TP53 at the very end of its DNA-binding domain (DBD) in a sample from an Indian oral cancer patient. Although the P152Lp53 DBD alone bound to DNA, the full-length protein completely lacked binding ability at its cognate DNA motifs. Interestingly, P152Lp53 could efficiently tetramerize, and the mutation had only a limited impact on the structure and stability of full-length p53. Significantly, when we expressed this variant in a TP53-null cell line, it induced cell motility, proliferation, and invasion compared with a vector-only control. Also, enhanced tumorigenic potential was observed when P152Lp53-expressing cells were xenografted into nude mice. Investigating the effects of P152Lp53 expression on cellular pathways, we found that it is associated with up-regulation of several pathways, including cell-cell and cell-extracellular matrix signaling, epidermal growth factor receptor signaling, and Rho-GTPase signaling, commonly active in tumorigenesis and metastasis. Taken together, our findings provide a detailed account of the biochemical and cellular alterations associated with the cancer-associated P152Lp53 variant and establish it as a gain-of-function TP53 variant.

Item Type:	Journal Article
Publication:	JOURNAL OF BIOLOGICAL CHEMISTRY
Publisher:	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Additional Information:	Copyright of this article belongs to AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Keywords:	carcinogenesis; tumor suppressor gene; tumor cell biology; gene expression; DNA-binding protein; gain-of-function mutant; P152Lp53; p53 tetramerization; transcriptional regulator
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	18 Dec 2019 07:07
Last Modified:	18 Dec 2019 07:07
URI:	http://eprints.iisc.ac.in/id/eprint/63854

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