Abstract
The p53 roles have been largely described; among them, cell proliferation and apoptosis control are some of the best studied and understood. Interestingly, the mutations on the six hotspot sites within the region that encodes the DNA-binding domain of p53 give rise to other very different variants. The particular behavior of these variants led to consider p53 mutants as separate oncogene entities; that is, they do not retain wild type functions but acquire new ones, namely Gain-of-function p53 mutants. Furthermore, recent studies have revealed how p53 mutants regulate gene expression and exert oncogenic effects by unbalancing specific microRNAs (miRNAs) levels that provoke epithelial-mesenchymal transition, chemoresistance, and cell survival, among others. In this review, we discuss recent evidence of the crosstalk between miRNAs and mutants of p53, as well as the consequent cellular processes dysregulated.
Highlights
The miRNAs are short non-coding RNAs that function as post-transcriptional regulators of gene expression. (Jansson and Lund, 2012)
The astonishing fact that some miRNAs behave differently according to the cellular context opens a new research path to explore; one possible explanation may come from observations of Vasudevan and others
They observed that microRNAs could make a switch that activates the protein expression depending on the cellular environment instead of silencing a target gene (Vasudevan et al, 2007)
Summary
The miRNAs are short non-coding RNAs that function as post-transcriptional regulators of gene expression. (Jansson and Lund, 2012). Given the outstanding capability of this transcription factor to promote invasion and metastasis by inducing EMT (Zhang et al, 2015), the authors provided evidence of the induction of metastatic-associated genes such as SPP1, MMP2, and MMP9 as well as EMT-promoting genes like ZEB1, BMI1, CDH2 (N-cadherin) and VIM (Vimentin) in the presence of p53 mutants (Dong et al, 2013) These data demonstrate that p53 GOF mutants downregulate miR-130b expression, which results in activation of ZEB1, and its downstream pathway contributes to the induction of EMT and increased EC cell invasion (Dong et al, 2013) (Figure 4B; Table 1). Subramanian and others sequenced small RNAs from the p53-null H1299 lung cancer cell line, stably transfected with the hotspot aggressive mutant p53R273H (32) In this approach, they observed 38 miRNAs up- and three downregulated; the tumor suppressor let-7i was abundant in the control cells but significantly down-regulated in H1299 cells expressing p53R273H. This oncomiR triggers the EMT program, involving the TGF-β pathway, through the repression of the tumor suppressor ZNF652 (Neilsen et al, 2013) (Figure 5B; Table 1)
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