| First Author | Iqbal N | Year | 2014 |
| Journal | Cell Cycle | Volume | 13 |
| Issue | 5 | Pages | 792-800 |
| PubMed ID | 24401748 | Mgi Jnum | J:218583 |
| Mgi Id | MGI:5617937 | Doi | 10.4161/cc.27725 |
| Citation | Iqbal N, et al. (2014) miR-34a is essential for p19(Arf)-driven cell cycle arrest. Cell Cycle 13(5):792-800 |
| abstractText | The Arf tumor suppressor gene product, p19(Arf), regulates cell proliferation in incipient cancer cells and during embryo development. Beyond its commonly accepted p53-dependent actions, p19(Arf) also acts independently of p53 in both contexts. One such p53-independent effect with in vivo relevance includes its repression of Pdgfrbeta, a process that is essential for vision in the mouse. We have utilized cell culture-based and mouse models to define a new role for miR-34a in this process. Ectopic expression of Arf in cultured cells enhanced the expression of several microRNAs predicted to target Pdgfrss synthesis, including the miR-34 family. Because miR-34a has been implicated as a p53-dependent effector, we investigated whether it also contributed to p53-independent effects of p19(Arf). Indeed, in mouse embryo fibroblasts (MEFs) lacking p53, Arf-driven repression of Pdgfrbeta and its blockade of Pdgf-B stimulated DNA synthesis were both completely interrupted by anti-microRNA against miR-34a. Ectopic miR-34a directly targeted Pdgfrbeta and a plasmid reporter containing wild-type Pdgfrbeta 3'UTR sequence, but not one in which the miR-34a target sequence was mutated. Although miR-34a expression has been linked to p53-a well-known effector of p19(Arf)-Arf expression and its knockdown correlated with miR-34a level in MEFs lacking p53. Finally, analysis of the mouse embryonic eye demonstrated that Arf controlled expression of miR-34a, and the related miR-34b and c, in vivo during normal mouse development. Our findings indicate that miR-34a provides an essential link between p19(Arf) and its p53-independent capacity to block cell proliferation driven by Pdgfrbeta. This has ramifications for developmental and tumor suppressor roles of Arf. |
