Hif-2alpha mediates UV-induced apoptosis through a novel ATF3-dependent death pathway.
In this study, we describe a novel activating transcription factor 3 (ATF3)-dependent death pathway triggered by ultraviolet (UV) irradiation. We demonstrate that ATF3 contributes to UV-induced apoptosis through the regulation of hypoxia inducible factor (Hif)-2alpha expression, which in turn induces the expression of proapoptotic genes, such as Caspase7 or TRAIL (tumor necrosis factor (ligand) superfamily, member 10). Gain of function of Hif-2alpha as well as ATF3 is sufficient to trigger cell death, whereas loss of function of both proteins drastically inhibits UV-induced apoptosis. Repression of Hif-2alpha strongly impairs ATF3-mediated death, providing evidences that Hif-2alpha is the major death effector of ATF3. In addition, Hif-1alpha, already known as a proapoptotic gene, upon UV irradiation, is not able to compensate for the lack of Hif-2alpha expression, thereby confirming the major contribution of Hif-2alpha in UV-mediated cell death. We further demonstrate that this cascade of gene activation depends on p38 and c-Jun N-terminal kinase (JNK) activity. Impairment of such a pathway is likely to contribute to oncogenesis by promoting survival of cells that could accumulate severe chromosomal alterations.
Turchi
L
L
INSERM U898, Nice F-06107, France.
Aberdam
E
E
Mazure
N
N
Pouysségur
J
J
Deckert
M
M
Kitajima
S
S
Aberdam
D
D
Virolle
T
T
D051700:Activating Transcription Factor 3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014466:Ultraviolet Rays; D000099162:Endothelial PAS Domain-Containing Protein 1
D051700:Activating Transcription Factor 3; D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C490449:ATF3 protein, human; C497442:HIF1A protein, human