title: p42/p44 mitogen-activated protein kinases activation is required for the insulin-like growth factor-I/insulin induced proliferation, but inhibits differentiation, in rat fetal brown adipocytes.
abstract: Insulin-like growth factor I (IGF-I)/insulin induced cytosolic p42/p44 mitogen-activated protein kinase (MAPK) activation in a time-dependent manner in fetal brown adipocytes, reaching a maximum at 5 min. Concurrently, nuclear p42/p44 MAPKs were also activated by IGF-I and insulin. This cytosolic and nuclear MAPK activation was totally prevented by pretreatment with the MAPK kinase (MEK1) inhibitor, PD98059. These results indicate that MEK mediates the IGF-I/insulin-induced p42/ p44 MAPK activation. IGF-I and insulin also increased the number of cells in the S + G2/M phases of the cell cycle, PCNA levels, and DNA synthesis at 24 h. This IGF-I/insulin-induced proliferation was completely blunted by the presence of MEK1 inhibitor. In contrast, inhibition of MEK1 potentiated the IGF-I-induced uncoupling protein (UCP-1) and the insulin-induced fatty acid synthase mRNAs expression after short and long-term treatments. Moreover, transient expression of a transfected active MEK construct (R4F) decreased IGF-I-induced UCP-1 and insulin-induced fatty acid synthase mRNA expression. These results demonstrate that p42/p44 MAPKs are essential intermediates for the IGF-I/insulin-induced mitogenesis, but may have a negative role in the regulation of adipocytic and thermogenic differentiation in brown adipocytes.
authors.affiliation: Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Ciudad Universitaria, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Porras
authors.forename: A M
authors.initials: AM
authors.lastname: Alvarez
authors.forename: A
authors.initials: A
authors.lastname: Valladares
authors.forename: M
authors.initials: M
authors.lastname: Benito
mesh_terms: D002001:Adipose Tissue, Brown / Q000166:cytology / Q000187:drug effects* / Q000196:embryology; D000818:Animals; D001833:Body Temperature Regulation / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002453:Cell Cycle; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D004790:Enzyme Induction; D064429:Fatty Acid Synthases / Q000096:biosynthesis / Q000235:genetics; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats
chemical_list: D007328:Insulin; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D064429:Fatty Acid Synthases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases