Abstract
MicroRNAs belonging to the miR-34 family have been proposed as critical modulators of the p53 pathway and potential tumor suppressors in human cancers. To formally test these hypotheses, we have generated mice carrying targeted deletion of all three members of this microRNA family. We show that complete inactivation of miR-34 function is compatible with normal development in mice. Surprisingly, p53 function appears to be intact in miR-34–deficient cells and tissues. Although loss of miR-34 expression leads to a slight increase in cellular proliferation in vitro, it does not impair p53-induced cell cycle arrest or apoptosis. Furthermore, in contrast to p53-deficient mice, miR-34–deficient animals do not display increased susceptibility to spontaneous, irradiation-induced, or c-Myc–initiated tumorigenesis. We also show that expression of members of the miR-34 family is particularly high in the testes, lungs, and brains of mice and that it is largely p53-independent in these tissues. These findings indicate that miR-34 plays a redundant function in the p53 pathway and suggest additional p53-independent functions for this family of miRNAs.
Highlights
The tumor-suppressor protein p53 is a master regulator of the stress response and provides a key barrier to cellular transformation and tumorigenesis [1]
MicroRNA deregulation is a common feature of human cancers, and numerous miRNAs have oncogenic or tumor suppressive properties
We focused on the three bestcharacterized p53-dependent processes: replicative senescence, response to DNA damage, and response to oncogene activation [31,32,33,34,35]
Summary
The tumor-suppressor protein p53 is a master regulator of the stress response and provides a key barrier to cellular transformation and tumorigenesis [1]. Three highly related miRNAs—miR-34a, miR-34b, and miR-34c (Figure 1A)—are directly induced upon p53 activation in multiple cell types and have been proposed to modulate p53 function [13,14,15,16,17,18,19,20]. The precursors of these miRNAs are transcribed from two distinct loci: the miR-34a locus on chromosome 1p36 and the miR-34b,c locus on chromosome 11q23. Canonical p53-binding sites are located in the promoter regions of both miR-34a and miR-34b,c, and these miRNAs are bona fide direct transcriptional targets of p53 [13,17,18]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have