Transcriptional Repression of miR-34 Family Contributes to p63-Mediated Cell Cycle Progression in Epidermal Cells

Abstract

p63, a p53 family member, is highly expressed in the basal proliferative compartment of the epidermis and its expression has been correlated with the growth ability and regenerative capacity of keratinocytes. In this study we report a mechanism through which p63 maintains cell cycle progression by directly repressing miR-34a and miR-34c. In the absence of p63, increased levels of miR-34a and miR-34c were observed in primary keratinocytes and in embryonic skin, with concomitant G1-phase arrest and inhibition of the cell cycle regulators cyclin D1 and cyclin-dependent kinase 4 (Cdk4). p63 directly bound to p53-consensus sites in both miR-34a and miR-34c regulatory regions and inhibited their activity. Concomitant downregulation of miR-34a and miR-34c substantially restored cell cycle progression and expression of cyclin D1 and Cdk4. Our data indicate that specific miR-34 family members have a significant role downstream of p63 in controlling epidermal cell proliferation.

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

“…[21][22][23][24][25][26][27][28][29] Thus, we asked whether p53 is also activated in p63 À / À MEFs. However, neither p53 protein nor its sensitive targets p21 and miR34a/b/c, also known reprogramming barriers, [40][41][42][43] (Figure 5g). Moreover, the tumor suppressors p19-Arf and p16-Ink4A, which are known reprogramming barriers in mouse and human fibroblasts, 23,24 were shown to partially mediate skin and limb defects of p63 À / À mice.…”

p53/p63/p73 in the Epidermis in Health and Disease

“…Global effects of p63 on microRNAs are realized via direct regulation and transactivation of the Dicer promoter by TAp63 (Su et al 2010) and the DiGeorge syndrome critical region gene 8 (DGCR8) promoter by DNp63 (Chakravarti et al 2014). In addition, p63 negatively regulates expression of several microRNAs of the miR-34 family, which show reciprocal expression patterns with p63 in the epidermis (Antonini et al 2010). Furthermore, p63 directly inhibits expression of miR-138, miR-181a/b, and miR130b in primary human keratinocytes (Rivetti di Val Cervo et al 2012).…”

Macro-management of microRNAs in cell cycle progression of tumor cells and its implications in anti-cancer therapy

“…Additionally, enforced expression of miR34a in K562 cells inhibits proliferation and G 1 /S transition by targeting CDK4 and CDK6 [33] . Another p53 family member, p63 positively regulates cell cycle progression by repressing the expression of miR34a and miR34c [34] . In the absence of p63, miR-34a and miR-34c are increased in primary keratinocytes and embryonic skin, with concomitant G 1 arrest and inhibition of the cell cycle regulators cyclin D1 and CDK4 [34] .…”

“…Another p53 family member, p63 positively regulates cell cycle progression by repressing the expression of miR34a and miR34c [34] . In the absence of p63, miR-34a and miR-34c are increased in primary keratinocytes and embryonic skin, with concomitant G 1 arrest and inhibition of the cell cycle regulators cyclin D1 and CDK4 [34] . Taken together, these data indicate that the miR-34 family modulates the expression of various cell cycle-related genes and is therefore important in the cell cycle progression of numerous cell types.…”