Journal of Investigative Dermatology vol:130 issue:9 pages:2269-2276
The signal transduction pathways leading to apoptosis of human keratinocytes responding to ultraviolet B (UVB) irradiation are complex and not completely understood. Previously, we reported that in UVB-irradiated keratinocytes, p38MAPK instigates Bax activation and mitochondrial apoptosis. However, the molecular mechanism underlying the pro-apoptotic function of p38MAPK remained unclear. Here, we show that in UVB-treated human primary keratinocytes the activation of p38MAPK is necessary to upregulate Noxa, a BH3-only pro-apoptotic dominantly induced by UVB and required for apoptosis. Whereas p53-silencing was marginally cytoprotective and poorly affected Noxa expression, p38MAPK inhibition in p53-silenced keratinocytes or in p53-/- cells could still efficiently prevent Noxa induction and intrinsic apoptosis following UVB, indicating that p38MAPK signals mainly through p53-independent mechanisms. Furthermore, p38MAPK was required for the induction and activation of HIF-1 in response to UVB and HIF-1 knockdown reduced Noxa expression and apoptosis. In UVB-irradiated keratinocytes Noxa targeted the anti-apoptotic Mcl-1 for degradation and siRNA-mediated knockdown of Noxa or p38MAPK inhibition restored levels of Mcl-1 and abolished apoptosis. Thus the pro-apoptotic mechanisms orchestrated by p38MAPK in human keratinocytes in response to UVB involve a HIF-1-Noxa axis, which prompts the downregulation of anti-apoptotic Mcl-1, thereby favouring Bax-mediated mitochondrial apoptosis of UVB-damaged keratinocytes.