JNK mediates UVB-induced apoptosis upstream lysosomal membrane permeabilization and Bcl-2 family proteins.
UVB irradiation induced phosphorylation of JNK and subsequent apoptosis in human melanocytes. Depletion of both JNK1 and JNK2 expression using siRNA transfection, protected against apoptosis, as detected by decreased nuclear fragmentation and caspase-3 activity, as well as reduced translocation of Bax to mitochondria. Moreover, release of cathepsin B and D from lysosomes to the cytosol was reduced when JNK expression was suppressed by siRNA, demonstrating a JNK dependent regulation of lysosomal membrane permeabilization. In unirradiated control melanocytes, coimmunoprecipitation showed that Bim was sequestered by Mcl-1, which had a pro-survival function. After UVB irradiation, a significant decrease in Mcl-1 protein level was found, which was prevented by addition of a proteasome inhibitor. The interaction between Bim and Mcl-1 was reduced in response to UVB irradiation and Bim was phosphorylated in a JNK dependent manner. In conclusion, these findings suggest JNK to have an important pro-apoptotic function following UVB irradiation in human melanocytes, by acting upstream of lysosomal membrane permeabilization and Bim phosphorylation.
Bivik
Cecilia
C
Division of Dermatology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, 581 85 Linköping, Sweden. cecbi@ibk.liu.se
Ollinger
Karin
K
D017209:Apoptosis / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival / Q000528:radiation effects; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007425:Intracellular Membranes / Q000528:radiation effects*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism* / Q000528:radiation effects*; D008297:Male; D008544:Melanocytes / Q000166:cytology / Q000201:enzymology / Q000528:radiation effects; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010539:Permeability / Q000528:radiation effects; D010766:Phosphorylation / Q000528:radiation effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000528:radiation effects; D021381:Protein Transport / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D014466:Ultraviolet Rays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D048031:JNK Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex