title: Cdc42GAP regulates c-Jun N-terminal kinase (JNK)-mediated apoptosis and cell number during mammalian perinatal growth.
abstract: Rho family GTPase Cdc42 is known to regulate polarity and growth in lower eukaryotes, but its physiologic function in mammals has yet to be determined. Here we have disrupted cdc42gap, a ubiquitously expressed negative regulator of Cdc42, in mice. Cdc42GAP(-/-) embryonic fibroblasts and various organs displayed significantly elevated Cdc42 activity. The embryonic and neonatal homozygous mice were reduced in size by approximately 25-40% and suffered severe growth retardation. Major organs from Cdc42GAP(-/-) mice were proportionally smaller because of decreased cell number. Basal apoptosis was increased in Cdc42GAP(-/-) cells and tissues, and this was attributed to altered c-Jun N-terminal kinase apoptotic signals. These results reveal a role of Cdc42GAP in mammalian perinatal growth and implicate the c-Jun N-terminal kinase-mediated apoptosis machinery as a Cdc42 effector pathway in vivo.
authors.affiliation: Division of Experimental Hematology, Children's Hospital Medical Center, Molecular Developmental Biology Graduate Program, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Linda
authors.initials: L
authors.lastname: Yang
authors.forename: Kevin
authors.initials: K
authors.lastname: Burns
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Kuan
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis; D049628:Body Size / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048670:MAP Kinase Kinase 4; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C505158:Arhgap1 protein, mouse; D020690:GTPase-Activating Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020764:cdc42 GTP-Binding Protein