microRNAs join the p53 network--another piece in the tumour-suppression puzzle

Abstract

Several recent studies have found a conserved microRNA (miRNA) family, the miR-34s, to be direct transcriptional targets of p53. miR-34 activation can recapitulate elements of p53 activity, including induction of cell-cycle arrest and promotion of apoptosis, and loss of miR-34 can impair p53-mediated cell death. These data reinforce the growing awareness that non-coding RNAs are key players in tumour development by placing miRNAs in a central role in a well-known tumour-suppressor network.

Figure 1. Current model of miRNA biogenesis and post-transcriptional silencing

Nascent transcripts of microRNA (miRNA) genes are processed by microprocessor into a stem-loop precursor, which is further processed by Dicer into a mature miRNA duplex, which often displays imperfect base-pairing. One strand of the miRNA duplex gets incorporated into the effector complex RISC (RNA-induced silencing complex), which recognizes specific targets through imperfect base-pairing and induces post-transcriptional gene silencing. Several mechanisms have been proposed for this mode of regulation: miRNAs can induce the repression of translation initiation, mark target mRNAs for degradation by deadenylation, or sequester targets into the cytoplasmic P-body.

Figure 2. A model of the p53–miR- 34 network in regulating cell proliferation and cell death

miR-34 is a direct transcriptional target of p53, which in turn downregulates genes required for proliferation and survival. Along with other p53 targets, such as p21 and BAX, miR-34-family miRNAs promote growth arrest and cell death in response to cancer related stress. ATM, ataxia talangiectasia mutated; ATR, ataxia telengiectasia and RAD3-related; CDK, cyclin-dependent kinase; CHK, checkpoint kinase