title: Nerve growth factor-induced cell cycle reentry in newborn neurons is triggered by p38MAPK-dependent E2F4 phosphorylation.
abstract: Cumulative evidence indicates that activation of cyclin D-dependent kinase 4/6 (cdk4/6) represents a major trigger of cell cycle reentry and apoptosis in vertebrate neurons. We show here the existence of another mechanism triggering cell cycle reentry in differentiating chick retinal neurons (DCRNs), based on phosphorylation of E2F4 by p38(MAPK). We demonstrate that the activation of p75(NTR) by nerve growth factor (NGF) induces nuclear p38(MAPK) kinase activity, which leads to Thr phosphorylation and subsequent recruitment of E2F4 to the E2F-responsive cdc2 promoter. Inhibition of p38(MAPK), but not of cdk4/6, specifically prevents NGF-dependent cell cycle reentry and apoptosis in DCRNs. Moreover, a constitutively active form of chick E2F4 (Thr261Glu/Thr263Glu) stimulates G(1)/S transition and apoptosis, even after inhibition of p38(MAPK) activity. In contrast, a dominant-negative E2F4 form (Thr261Ala/Thr263Ala) prevents NGF-induced cell cycle reactivation and cell death in DCRNs. These results indicate that NGF-induced cell cycle reentry in neurons depends on the activation of a novel, cdk4/6-independent pathway that may participate in neurodegeneration.
authors.affiliation: Department of Molecular, Cellular, and Developmental Neurobiology, Cajal Institute, IC-CSIC, Madrid, Spain.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Morillo
authors.forename: Erika P
authors.initials: EP
authors.lastname: Abanto
authors.forename: María J
authors.initials: MJ
authors.lastname: Román
authors.forename: José M
authors.initials: JM
authors.lastname: Frade
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D019943:Amino Acid Substitution; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D002645:Chickens; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D050704:E2F4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D030161:Avian Proteins; D018076:DNA, Complementary; D050704:E2F4 Transcription Factor; D020800:Receptor, Nerve Growth Factor; D011994:Recombinant Proteins; D020932:Nerve Growth Factor; D016203:CDC2 Protein Kinase; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D048051:p38 Mitogen-Activated Protein Kinases