Induction of apoptosis-like mitochondrial impairment triggers antioxidant and Bcl-2-dependent keratinocyte differentiation.
Terminally differentiated keratinocytes are dead enucleated squams. We showed previously that the mitochondria-dependent cell death pathway might be gradually activated as differentiation progresses. In this study, we demonstrated that protoporphyrin IX, staurosporine, and rotenone induced apoptotic-like changes in the mitochondria, and early differentiation of keratinocytes without inducing apoptosis. Kinetics studies established that differentiation-related changes, including growth arrest, flattened morphology, stratification, and keratin 10 (K10) expression, were downstream of mitochondrial depolarization and proliferation, reactive oxygen species (ROS) production, and release of cytochrome c and apoptosis-inducing factor. When these changes were prevented by overexpressing Bcl-2 or pharmacologically decreasing the ROS level, K10 upregulation was inhibited, implying that the differentiated phenotype and K10 expression require apoptotic mitochondria, ROS being the most likely differentiation-mediating factor. Our data also suggest that the same mitochondria-affecting stimuli can induce either differentiation or apoptosis, depending on the keratinocyte's competency to undergo differentiation, a competency that may be controlled by Bcl-2.
Tamiji
Susan
S
INSERM U459, Faculté de Médecine, Lille Cedex, France.
Beauvillain
Jean-Claude
JC
Mortier
Laurent
L
Jouy
Nathalie
N
Tual
Martine
M
Delaporte
Emmanuel
E
Formstecher
Pierre
P
Marchetti
Philippe
P
Polakowska
Renata
R
D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D002118:Calcium / Q000502:physiology; D002454:Cell Differentiation; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000166:cytology*; D008928:Mitochondria / Q000473:pathology* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D011524:Protoporphyrins / Q000494:pharmacology; D017382:Reactive Oxygen Species; D012402:Rotenone / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology
D000975:Antioxidants; D019253:Proto-Oncogene Proteins c-bcl-2; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; D012402:Rotenone; D045304:Cytochromes c; C028025:protoporphyrin IX; D019311:Staurosporine; D002118:Calcium