Aging and chronic DNA damage response activate a regulatory pathway involving miR-29 and p53

Abstract

Aging is a multifactorial process that affects most of the biological functions of the organism and increases susceptibility to disease and death. Recent studies with animal models of accelerated aging have unveiled some mechanisms that also operate in physiological aging. However, little is known about the role of microRNAs (miRNAs) in this process. To address this question, we have analysed miRNA levels in Zmpste24-deficient mice, a model of Hutchinson-Gilford progeria syndrome. We have found that expression of the miR-29 family of miRNAs is markedly upregulated in Zmpste24 À/À progeroid mice as well as during normal aging in mouse. Functional analysis revealed that this transcriptional activation of miR-29 is triggered in response to DNA damage and occurs in a p53-dependent manner since p53 À/À murine fibroblasts do not increase miR-29 expression upon doxorubicin treatment. We have also found that miR-29 represses Ppm1d phosphatase, which in turn enhances p53 activity. Based on these results, we propose the existence of a novel regulatory circuitry involving miR-29, Ppm1d and p53, which is activated in aging and in response to DNA damage.

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene‐induced lung tumors in aged mice

“…The p53 damage response has been shown to decline with age in response to DNA damage in spleen and thymus of mice (Feng et al ., 2007). In other studies, p53 activity was found to be upregulated in noncancerous tissues of aged mice (Edwards et al ., 2007; Ugalde et al ., 2011). We found a less efficient p53 tumor suppressor response, as measured by protein expression, in lung adenomas and hyperplasias from old Kras G12D mice.…”

Down-regulation of Wild-type p53-induced Phosphatase 1 (Wip1) Plays a Critical Role in Regulating Several p53-dependent Functions in Premature Senescent Tumor Cells

“…Interestingly, persistent DNA damage results in Wip1 down-regulation also in MCF-7 cells, which overexpress the phosphatase as a consequence of gene amplification. Repression of Wip1 protein during chronic DDR and in pathological aging has been recently demonstrated in a mouse model of progeria (42). In this model, suppression of Wip1 has been related to miR-29 up-regulation (42).…”

miR-29 Promotes Murine Osteoclastogenesis by Regulating Osteoclast Commitment and Migration

“…These data contribute to our understanding of the basic mechanisms regulating osteoclast differentiation and provide insight into the function of miR-29 family members in cells of the hematopoietic lineage and in other tissue types. Dysregulation of miR-29 family members is implicated in the pathology of multiple malignancies and in conditions such as diabetes and fibrosis, and aging (63). Additional studies, in vivo, will better define the role of miR-29 in osteoclastogenesis.…”