Ultraviolet B irradiation up-regulates MM1 and induces photoageing of the epidermis.

Abstract

ΔNp63α and c-Myc are key transcription factors controlling proliferation and senescence in epithelial cells. We previously reported that the c-Myc modulator MM1 and its E3 ligase, HERC3, together with the transcription factor ΔNp63α, compose a feedback loop, which regulates proliferative senescence in MCF-10A mammary epithelial cells. However, it is unknown whether this loop is involved in skin ageing. On the other hand, ultraviolet B (UVB) rays are assumed to be the main culprits for photoageing of the epidermis, but the underlying mechanisms are obscure. To investigate whether MM1/ΔNp63α axis is involved in UVB-induced photoageing of the epidermis. HaCaT human immortalized keratinocytes overexpressed with MM1, knocked down with c-Myc or irradiated with UVB, were subjected to MTT assays to measure cell proliferation, as well as RT-qPCR or immunoblot to detect the members of MM1/ΔNp63α loop and the cellular senescence markers. Meanwhile, primary normal human keratinocytes (NHKs) or mice were irradiated with UVB, followed by immunoblot analysis, SA-β-gal, haematoxylin-eosin or immunohistochemistry staining. Overexpression of MM1 down-regulated ΔNp63α and induced proliferative senescence in the HaCaT cells. In the HaCaT cells, NHKs and the mouse epidermis, UVB irradiation increased MM1 mRNA level and led to a down-regulation of ΔNp63α, HERC3 and c-Myc, concomitant with cellular senescence or photoageing. Additionally, knock-down of c-Myc induced proliferative senescence in the HaCaT cells and abrogated UVB-induced cellular senescence. UVB up-regulates MM1 and consequently modulates ΔNp63α and c-Myc, which may account for the proliferative senescence of keratinocytes and photoageing of the epidermis.