title: A p38(MAPK)/HIF-1 pathway initiated by UVB irradiation is required to induce Noxa and apoptosis of human keratinocytes.
abstract: 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, p38(MAPK) instigates Bcl-2-associated X protein (Bax) activation and mitochondrial apoptosis. However, the molecular mechanism underlying the pro-apoptotic function of p38(MAPK) remained unclear. Here, we show that in UVB-treated human primary keratinocytes the activation of p38(MAPK) 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, p38(MAPK) inhibition in p53-silenced keratinocytes or in p53(-/-) cells could still efficiently prevent Noxa induction and intrinsic apoptosis after UVB, indicating that p38(MAPK) signals mainly through p53-independent mechanisms. Furthermore, p38(MAPK) 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 p38(MAPK) inhibition restored levels of Mcl-1 and abolished apoptosis. Thus, the pro-apoptotic mechanisms orchestrated by p38(MAPK) 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.
authors.affiliation: Cell Death Research and Therapy Laboratory, Department of Molecular Cell Biology, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Nys
authors.forename: An
authors.initials: A
authors.lastname: Van Laethem
authors.forename: Carine
authors.initials: C
authors.lastname: Michiels
authors.forename: Noemi
authors.initials: N
authors.lastname: Rubio
authors.forename: Jacques G
authors.initials: JG
authors.lastname: Piette
authors.forename: Maria
authors.initials: M
authors.lastname: Garmyn
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agostinis
mesh_terms: D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D001549:Benzamides; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology / Q000528:radiation effects; D020935:MAP Kinase Signaling System / Q000502:physiology / Q000528:radiation effects*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*; D015854:Up-Regulation / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C494826:BAX protein, human; D001549:Benzamides; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C023957:triflumuron; D048051:p38 Mitogen-Activated Protein Kinases