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Activation of p38 MAPK is required for Bax translocation to mitochondria, cytochrome c release and apoptosis induced by UVB irradiation in human keratinocytes
Author(s) -
Van Laethem An,
Van Kelst Sofie,
Lippens Saskia,
Declercq Wim,
Vandenabeele Peter,
Janssens Stefan,
Vandenheede Jackie R.,
Garmyn Maria,
Agostinis Patrizia
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2285fje
Subject(s) - p38 mitogen activated protein kinases , microbiology and biotechnology , cytochrome c , mapk/erk pathway , apoptosis , mitochondrion , caspase , programmed cell death , chemistry , mitochondrial apoptosis induced channel , biology , kinase , biochemistry
This study establishes that activation of p38 MAPK by UVB represents a crucial signal required for the conformational change and translocation of Bax to the mitochondria in human keratinocytes. UVB‐induced Bax translocation and mitochondrial cytochrome c release, which precede caspase activation and other endpoints of the apoptotic program such as chromatin fragmentation and loss of mitochondrial transmembrane potential, are blocked by genetic or pharmacological inhibition of the p38α MAPK. Inhibition of p38 MAPK strongly reduces the UVB‐induced formation of sunburn cells and blocks Bax conformational change both in cultured human keratinocytes and in human skin, providing clear evidence for the physiological role of the p38 MAPK‐Bax pathway in the removal of precancerous, UVB‐damaged keratinocytes. Furthermore, we show that Bcl‐2 overexpression, but not the pan‐caspase inhibitor zVAD‐fmk, blocks Bax conformational change and its subsequent translocation downstream of p38 MAPK. These data indicate that the activation of p38 MAPK by UVB engages a caspase‐independent death signal leading to mitochondrial membrane permeabilization and apoptosis in human keratinocytes and suggest that p38 MAPK might have a preventive role in the process of photocarcinogenesis.