title: Apoptosis signal-regulating kinase1 is inducible by protein kinase Cδ and contributes to phorbol ester-mediated G1 phase arrest through persistent JNK activation.
abstract: Although protein kinase Cδ (PKCδ) has been suggested in the negative control of the cell cycle machinery in many types of cancer cells, its underlying mechanisms are partly understood. Here we report that the expression of apoptosis signal-regulating kinase1 (ASK1) is inducible in a PKCδ-dependent manner, and contributes to phorbol ester-induced cell cycle arrest through persistent JNK activation in breast cancer epithelial cells. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) gradually up-regulated the expression of ASK1 mRNA and protein, and subsequently enhanced its catalytic activity in MCF-7 cells. Importantly, such PMA-induced ASK1 expression was completely abolished by pretreatment of rottlerin, a specific PKCδ inhibitor or by knocking down the expression of PKCδ, while ectopic expression of a constitutively active form of PKCδ strongly up-regulated ASK1 expression. We also found that the persistent activation of mitogen-activated protein kinase, JNK in response to PMA was greatly attenuated by RNA interference-mediated knockdown of ASK1. Taken together, these results suggest that inducible expression of ASK1 by PKCδ contributes to the G1 arrest by enhancing persistent JNK signaling activation which represents a novel alternative mechanism of PKCδ-dependent cell cycle arrest and limiting proliferation of breast cancer epithelial cells.
authors.affiliation: Department of Pharmacology, Research Institute for Medical Science, Infection Signaling Network Research Center, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
authors.forename: Young-Rae
authors.initials: YR
authors.lastname: Kim
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Byun
authors.forename: Juhee
authors.initials: J
authors.lastname: Jeon
authors.forename: Byung Lyul
authors.initials: BL
authors.lastname: Choi
authors.forename: Kyeong Ah
authors.initials: KA
authors.lastname: Park
authors.forename: Minho
authors.initials: M
authors.lastname: Won
authors.forename: Tiejun
authors.initials: T
authors.lastname: Zhang
authors.forename: Sanghee
authors.initials: S
authors.lastname: Shin
authors.forename: Hyunji
authors.initials: H
authors.lastname: Lee
authors.forename: Junseo
authors.initials: J
authors.lastname: Oh
authors.forename: Gang Min
authors.initials: GM
authors.lastname: Hur
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D059585:G1 Phase Cell Cycle Checkpoints / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010703:Phorbol Esters / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D010703:Phorbol Esters; D034741:RNA, Small Interfering; C085746:rottlerin; D051745:Protein Kinase C-delta; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human