Title: A p38MAPK - HIF-1 pathway initiated by UVB irradiation is required to induce Noxa and apoptosis of human keratinocytes
Authors: Nys, Kris
Van Laethem, An
Michiels, Carine
Rubio Romero, Noemí
Piette, Jacques
Garmyn, Maria
Agostinis, Patrizia # ×
Issue Date: Sep-2010
Publisher: Elsevier Science Pub. Co.
Series Title: Journal of Investigative Dermatology vol:130 issue:9 pages:2269-2276
Abstract: 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.
ISSN: 0022-202X
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Dermatology
Laboratory of Cell Death Research & Therapy
× corresponding author
# (joint) last author

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