p53 and its mutants in tumor cell migration and invasion

Abstract

In about half of all human cancers, the tumor suppressor p53 protein is either lost or mutated, frequently resulting in the expression of a transcriptionally inactive mutant p53 protein. Loss of p53 function is well known to influence cell cycle checkpoint controls and apoptosis. But it is now clear that p53 regulates other key stages of metastatic progression, such as cell migration and invasion. Moreover, recent data suggests that expression of mutant p53 is not the equivalent of p53 loss, and that mutant p53s can acquire new functions to drive cell migration, invasion, and metastasis, in part by interfering with p63 function.

Metformin Blocks Melanoma Invasion and Metastasis Development in AMPK/p53-Dependent Manner

“…Indeed, this transcription factor is well-known as a potent suppressor of tumor development by inhibiting cell-cycle progression and promoting senescence, apoptosis, or autophagy (32,33). More recently, accumulating evidence has pointed an alternative role of p53 by negatively regulating invasion and tumor cell metastasis (8,34,35). In melanoma cells, metformin promotes the interaction between AMPKa and p53 and strongly stimulates p53 activity.…”

p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53

“…90 In the second mechanism, in H1299 human cells lacking TGFb receptors, a direct interaction between mutant p53 (175H; 273H) and p63 seems to occur, resulting in inhibition of p63-mediated regulation of integrin a5b1 and epidermal growth factor receptor endocytosis cycling. 12,89 It is unclear whether this effect is common to all p53 mutants or confined to a particular subset, but this would be important information to refine the clinical predictive value of p53 genotyping.…”

“…In addition to the full length a isoform, two isoforms have been described: a b isoform (skipping exon 13) and a g isoform (alternative exon 15, following exon 10, with its stop codon and distinct 3 0 -UTR. In silico analysis predicted the d isoform (skipping exon [12][13] and the e isoform (premature termination in intron 10 retaining the 5 0 -portion of intron 10 with a stop codon p63 is the most recently discovered but the most ancient member of the p53 family [8][9][10][11][12][13][14][15]28 ( Figure 1). As indicated above, p63 is transcribed from two promoters, giving rise to proteins that may (TAp63 isoforms) or may not (DNp63 isoforms) contain the TA, 1 and alternative splicing at the 3 0 -end produces additional proteins (a-e isoforms), 29 although there is no in vivo evidence for two latter isoforms.…”

Multifaceted functions of Siva-1: more than an Indian God of Destruction

“…Increasing evidence suggests that wide-type p53 opposes EMT and cell migration to prevent metastasis. However, mutant p53 appears to acquire additional functions to drive cell migration, invasion, and metastasis (Muller et al, 2011). Therefore the p53-Siva-1 feedback loop makes it particularly interesting to investigate whether Siva-1 mediates the inhibitory effect of p53 on tumor metastasis and whether the status of p53 affects the function of Siva-1 in regulating tumor metastasis.…”