p53-induced miRNAs upon CKIα ablation

Continuously renewing tissues are often divided into proliferative and post-mitotic differentiated zones, which must retain their function also following stress and damage. Here we show how p53 operates via its two effector arms miR-34a or p21 to control enterocyte proliferation along the crypt villus axis. Whereas cell cycle is commonly regulated via the Rb pathway by CDK inhibitors, we found that in the gut epithelium, crypt cell proliferation upon p53 activation is primarily controlled by miR-34a, regulating pRb phosphorylation via the Cyclin D/CDK4 complex. Surprisingly, p21 has little effect on pRb phosphorylation and crypt cell proliferation, yet functions to secure post-mitotic villus cell quiescence via the Rb-like (RBL) /E2F4 complex, implicating distinct functions of the Rb and RBL machineries in tissue renewal. It thus appears that mammalian2tissue control of the cell cycle is far more specialized than previously appreciated, providing new opportunities to target specific tissue components for therapeutic purposes. To assess a putative role of p53-induced miRNAs in regulating enterocyte proliferation upon CKIα ablation in the mouse gut (CKIαΔgut), we profiled the microRNAs in enterocytes purified from heterozygous CKIα+/Δgut control (CKIα Het), CKIαΔgut (CKIα KO) and doubly-deleted CKIα/p53Δgut (CKIα/p53 DKO) mice (n=3 per pooled group). Fold change of each miRNA expression in CKIαΔgut or CKIα/p53Δgut was relatively quantified (RQ) to CKIα Het specimens.