Cold-inducible RNA-binding protein (CIRP) induces translation of the cell-cycle inhibitor p27(Kip1)

The CDK inhibitor p27(Kip1) plays a central role in controlling cell proliferation and cell-cycle exit. p27(Kip1) protein levels oscillate during cell-cycle progression and are regulated by mitogen or anti-proliferative signaling. The abundance of the protein is frequently determined by post-transcriptional mechanisms including ubiquitin-mediated proteolysis and translational control. Here, we report that the cold-inducible RNA-binding protein (CIRP) selectively binds to the 5′ untranslated region of the p27(Kip1) mRNA. CIRP is induced, modified and relocalized in response to various stress stimuli and can regulate cell survival and cell proliferation particularly during stress. Binding of CIRP to the 5′UTR of the p27(Kip1) mRNA significantly enhanced reporter translation. In cells exposed to mild hypothermia, the induction of CIRP correlated with increased translation of a p27(Kip1) 5′UTR reporter and with the accumulation of p27(Kip1) protein. shRNA-mediated CIRP knockdown could prevent the induction of translation. We found that p27(Kip1) is central for the decreased proliferation at lower temperature, since p27(Kip1) KO mouse embryonic fibroblasts (MEFs) hardly increased their doubling time in hypothermic conditions, whereas wild-type MEFs significantly delayed proliferation in response to cold stress. This suggests that the CIRP-dependent p27(Kip1) upregulation during mild hypothermia contributes to the cold shock-induced inhibition of cell proliferation.