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.
Highlights
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
In one of the oral cancer samples, we found C Ͼ T nucleotide substitution, which leads to a change in the amino acid from proline to leucine at position 152 in the DNA-binding domain of p53 (Fig. 1b)
To predict a possible model of P152Lp53 interaction with the cognate DNA-binding site through the PyMOL-generated image, the coordinates of tumor suppressor p53 complexed with DNA (RCSB code 1TUP) were used
Summary
The cancer-associated, gain-of-function TP53 variant P152Lp53 activates multiple signaling pathways implicated in tumorigenesis. Missense mutations in TP53 can contribute to tumorigenesis through gain-of-function of biochemical and biological properties that stimulate tumor growth. P53 is the most well-studied mammalian transcription factor [1] It is biologically active as a homotetramer [2, 3] and cooperatively binds to its target DNA in a sequence-specific manner [4]. Apart from losing WT functions due to loss in DNA-binding activity of p53 and dominant-negative effects where mutant p53 forms mixed tetramer with coexpressed WT p53 and renders it incapable of DNA binding and transactivation [19]; missense mutations in p53 contribute to tumorigenesis through their novel “gain-of-function” effects where mutant p53 acquire new biochemical and biological properties [20, 21] and drives tumor growth through increased cell migration, invasion, proliferation, genomic instability, antiapoptosis, antineoplastic, therapy resistance etc. RNA-Seq analysis of tumor cell-derived RNA samples reveals unique gain-of-function pathways induced by P152Lp53
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