المؤلفون: Carine Michiels, Jacques Piette, Maria Garmyn, Kris Nys, Noemie Rubio, Patrizia Agostinis, An Van Laethem

المصدر: Journal of Investigative Dermatology. 130(9):2269-2276

مصطلحات موضوعية: Keratinocytes, MAPK/ERK pathway, Carcinoma, Squamus Cell, Skin Neoplasms, MAP Kinase Signaling System, Ultraviolet Rays, p38 mitogen-activated protein kinases, Apoptosis, Dermatology, Biology, p38 Mitogen-Activated Protein Kinases, Biochemistry, Downregulation and upregulation, Cell Line, Tumor, hemic and lymphatic diseases, Humans, Molecular Biology, bcl-2-Associated X Protein, Gene knockdown, integumentary system, Intrinsic apoptosis, RNA, Cell Biology, Hypoxia-Inducible Factor 1, alpha Subunit, Up-Regulation, Cell biology, Pro-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-bcl-2, Benzamides, Carcinoma, Squamous Cell, Myeloid Cell Leukemia Sequence 1 Protein, Tumor Suppressor Protein p53, Signal transduction

الوصف: The signal transduction pathways leading to apoptosis of human keratinocytes responding to ultraviolet B (UVB) irradiation are complex and not completely understood. Previously, we reported that in UVB-irradiated keratinocytes, p38MAPK instigates 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 following UVB, indicating that p38MAPK signals mainly through p53-independent mechanisms. Furthermore, p38MAPK was required for the induction and activation of HIF-1 in response to UVB and HIF-1 knockdown reduced Noxa expression and apoptosis. In UVB-irradiated keratinocytes Noxa targeted the anti-apoptotic Mcl-1 for degradation and 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 a HIF-1-Noxa axis, which prompts the downregulation of anti-apoptotic Mcl-1, thereby favouring Bax-mediated mitochondrial apoptosis of UVB-damaged keratinocytes. ispartof: Journal of Investigative Dermatology vol:130 issue:9 pages:2269-2276 ispartof: location:United States status: published

وصف الملف: Print-Electronic

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::253060a6ec7ada116f52d638a068b000Test

المؤلفون: Wilfried Merlevede, Jackie R. Vandenheede, Roger Bouillon, Maryan Garmyn, Patrizia Agostinis, Zerihun Assefa

المصدر: Scopus-Elsevier

مصطلحات موضوعية: Keratinocytes, MAPK/ERK pathway, MAP Kinase Kinase 4, Proto-Oncogene Proteins c-jun, Ultraviolet Rays, medicine.medical_treatment, Nerve Tissue Proteins, Human skin, Dermatology, Biochemistry, Cell Line, Epidermal growth factor, medicine, oxidative stress, Humans, RNA, Messenger, Molecular Biology, DNA Primers, Mitogen-Activated Protein Kinase Kinases, Base Sequence, Dose-Response Relationship, Drug, Epidermal Growth Factor, integumentary system, biology, Growth factor, c-jun, JNK Mitogen-Activated Protein Kinases, Dose-Response Relationship, Radiation, DNA, Cell Biology, Precipitin Tests, Molecular biology, Enzyme Activation, HaCaT, medicine.anatomical_structure, c-Jun N-terminal kinases, biology.protein, Mitogen-Activated Protein Kinases, Reactive Oxygen Species, Keratinocyte, Protein Kinases, Proto-Oncogene Proteins c-fos, hormones, hormone substitutes, and hormone antagonists, SAPKs, Signal Transduction

الوصف: Exposure of mammalian cells to solar ultraviolet (UV) radiation leads to the expression of several genes, and UV has been recognized as a major initiator and promoter of skin cancer. The component of the solar radiation that contributes most to human skin malignancy is UVB (280–320 nm) and, to a lesser extent, UVA (320–400 nm), whereas the high-energy UVC (100–280 nm) is absorbed by the earth's upper atmosphere. Sublethal doses of UVB produce strong induction of c- jun and c- fos transcripts in several cells including human primary keratinocytes. The present report confirms that this is also the case in the HaCaT cell line and shows that similar UVB doses are potent inducers of the JNK/SAPK family of mitogen-activated protein kinases but only weak activators of ERKs. Epidermal growth factor (EGF) caused rapid induction of both JNK- and ERK-signaling pathways, and the downmodulation of the EGF-signaling pathway by EGF pre-treatment inhibited the UVB-induced JNK1 activation. Prior UVB irradiation of the cells decreased the level of the ERK2 activation by a subsequent EGF treatment, but this sensitized the cells and allowed for the super-activation of JNK1 after a rechallenge with either UVB or EGF. The antioxidant N -acetylcysteine impaired the UVB- and EGF-induced activation of JNK1. Our data suggest the presence of shared signaling component(s) in the UVB- and EGF-induced cellular response pathways and imply that oxidative stress plays a significant role in the activation of JNK1 by UVB and EGF.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f123d6c76ebe7cce250a28a94729eb50Test
https://doi.org/10.1111/1523-1747.ep12292595Test