Résumé
The signal transduction pathways leading to apoptosis of human keratinocytes responding to UVB irradiation are
complex and not completely understood. Previously, we reported that in UVB-irradiated keratinocytes, p38MAPK
instigates Bcl-2-associated X protein (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 after UVB, indicating that p38MAPK signals
mainly through p53-independent mechanisms. Furthermore, p38MAPK was required for the induction and activation
of hypoxia-inducible factor 1 (HIF-1) in response to UVB, and HIF-1 knockdown reduced Noxa expression and
apoptosis. In UVB-irradiated keratinocytes, Noxa targeted the anti-apoptotic myeloid cell leukemia sequence
1 (Mcl-1) for degradation, and small-interfering RNA (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 an HIF-1/Noxa axis, which prompts the downregulation of
anti-apoptotic Mcl-1, thereby favoring Bax-mediated mitochondrial apoptosis of UVB-damaged keratinocytes.
langue originale | Anglais |
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Pages (de - à) | 2269-2276 |
Nombre de pages | 8 |
journal | Journal of Investigative Dermatology |
Volume | 130 |
Les DOIs | |
Etat de la publication | Publié - 2010 |
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