Positioning atypical protein kinase C isoforms in the UV-induced apoptotic signaling cascade.
Recent studies have documented the involvement of the atypical protein kinase C (aPKC) isoforms in important cellular functions such as cell proliferation and survival. Exposure of cells to a genotoxic stimulus that induces apoptosis, such as UV irradiation, leads to a profound inhibition of the atypical PKC activity in vivo. In this study, we addressed the relationship between this phenomenon and different proteins involved in the apoptotic response. We show that (i) the inhibition of the aPKC activity precedes UV-induced apoptosis; (ii) UV-induced aPKC inhibition and apoptosis are independent of p53; (iii) Bcl-2 proteins are potent modulators of aPKC activity; and (iv) the aPKCs are located upstream of the interleukin-converting enzyme-like protease system, which is required for the induction of apoptosis by both Par-4 (a selective aPKC inhibitor) and UV irradiation. We also demonstrate here that inhibition of aPKC activity leads to a decrease in mitogen-activated protein (MAP) kinase activity and simultaneously an increase in p38 activity. Both effects are critical for the induction of apoptosis in response to Par-4 expression and UV irradiation. Collectively, these results clarify the position of the aPKCs in the UV-induced apoptotic pathway and strongly suggest that MAP kinases play a role in this signaling cascade.
Berra
E
E
Laboratorio Glaxo Wellcome-CSIC de Biología Molecular y Cellular, Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Spain.
Municio
M M
MM
Sanz
L
L
Frutos
S
S
Diaz-Meco
M T
MT
Moscat
J
J
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D014466:Ultraviolet Rays
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C101296:prostate apoptosis response-4 protein; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003546:Cysteine Endopeptidases; D020170:Caspase 1