Intact p53-Dependent Responses in miR-34–Deficient Mice

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.

The Roles of MicroRNAs and Protein Components of the MicroRNA Pathway in Lung Development and Diseases

“…Conversely, miR-449 null mice developed normally, without gross defects. One of the explanations for the lack of phenotype is the compensatory role of miR-34 family members that share identical seed sequence and similar expression pattern with miR-449 (90,91). miR-34 family members are highly expressed in lungs and also increased in the process of ciliogenesis of HAECs (88,91).…”

“…Interestingly, the p53 pathway remains intact in miR-34 null mice. This is likely due to the redundancy of miR-449 or other p53 downstream effectors, such as Cdkn1a and BCL2-associated X protein that are working in parallel with miR-34 (91). Indeed, miR-34a deficiency strongly promotes tumorigenesis in a K-Ras-induced lung cancer when p53 is haploinsufficient, strongly suggesting a tumor suppressor activity for miR-34 (100).…”

miRNAs link metabolic reprogramming to oncogenesis

“…However their role as downstream effectors of p53 is currently under debate. A recent report investigating the role of miR-34 in the intact mouse showed that mir-34 knockouts remain healthy with no spontaneous tumors [134].…”

Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice

“…This apparent disconnect between the in vitro effects and in vivo relevance extends to other miRNAs. For instance, knock-out of miR-34a in mice showed no abnormalities in p53 function (Concepcion et al 2012) in spite of several in vitro studies supporting its role in the p53-mediated apoptosis (He et al 2007). Also, correlation studies in disease patient samples point to molecular changes which not only contribute to pathogenesis but also those which could occur as a result of compensatory mechanisms.…”