title: Gq protein-induced apoptosis is mediated by AKT kinase inhibition that leads to protein kinase C-induced c-Jun N-terminal kinase activation.
abstract: G(q) protein-coupled receptors (G(q)PCRs) regulate various cellular processes, including mainly proliferation and differentiation. In a previous study we found that in prostate cancer cells, the G(q)PCR of gonadotropin-releasing hormone (GnRH) induces apoptosis by reducing the PKC-dependent AKT activity and elevating JNK phosphorylation. Because it was thought that G(q)PCRs mainly induce activation of AKT, we first undertook to examine how general this phenomenon is. In a screen of 21 cell lines we found that PKC activation results in the reduction of AKT activity, which correlates nicely with JNK activation and in some cases with apoptosis. To understand further the signaling pathways involved in this stimulation, we studied in detail SVOG-4O and αT3-1 cells. We found that prostaglandin F2α and GnRH agonist (GnRH-a) indeed induce significant Gα(q)- and PKC-dependent apoptosis in these cells. This is mediated by two signaling branches downstream of PKC, which converge at the level of MLK3 upstream of JNK. One branch consists of c-Src activation of the JNK cascade, and the second involves reduction of AKT activity that alleviates its inhibitory effect on MLK3 to allow the flow of the c-Src signal to JNK. At the MAPKK level, we found that the signal is transmitted by MKK7 and not MKK4. Our results present a general mechanism that mediates a G(q)PCR-induced, death receptor-independent, apoptosis in physiological, as well as cancer-related systems.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Ben-Ami
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Naor
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: rony.seger@weizmann.ac.il.
authors.forename: Rony
authors.initials: R
authors.lastname: Seger
mesh_terms: D000818:Animals; D017209:Apoptosis; D002021:Buffers; D019556:COS Cells; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D002021:Buffers; D007987:Gonadotropin-Releasing Hormone; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11