Nerve growth factor-induced cell cycle reentry in newborn neurons is triggered by p38MAPK-dependent E2F4 phosphorylation.

Molecular and Cellular Biology
Sandra M MorilloJosé María Frade

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.

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Citations

Jan 16, 2015·Cell Cycle·José M Frade, María C Ovejero-Benito
Aug 30, 2016·The Journal of Reproduction and Development·Hiroyuki ImaiKiyoshi Kano
Oct 27, 2017·Aging·José M Frade, Noelia López-Sánchez
Apr 21, 2018·Interdisciplinary Sciences, Computational Life Sciences·Jieyuan DingShuaiqun Wang
Jun 13, 2017·Nucleic Acids Research·Iris Patiño-ParradoJosé M Frade
Oct 24, 2017·Journal of Huazhong University of Science and Technology. Medical Sciences = Hua Zhong Ke Ji Da Xue Xue Bao. Yi Xue Ying De Wen Ban = Huazhong Keji Daxue Xuebao. Yixue Yingdewen Ban·Li BaMin Zhang
Nov 18, 2020·Cellular and Molecular Neurobiology·Mingming ChenHong Liao
Feb 10, 2016·Molecular Cancer Research : MCR·Chao ChengFrederick S Varn

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