Activation of the BRCA1/Chk1/p53/p21^Cip1/Waf1 pathway by nitric oxide and cell cycle arrest in human neuroblastoma NB69 cells

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• 作者：Marlies Van de Wouwer¹ ; Cé ; lia Couzinié ; ² ; Miguel Serrano-Palero³ ; Ó ; scar Gonzá ; lez-Ferná ; ndez ; Clara Galmé ; s-Varela ; Paula Mené ; ndez-Antolí ; Laura Grau ; Antonio Villalobo ; ^{antonio.villalobo@iib.uam.es}
• 关键词：AEBSF ; 4-(2-aminoethyl)-benzenesulfonyl fluoride ; ATM ; ataxia telangiectasia mutated ; ATR ; AT- and Rad3-related ; BRCA1 ; breast cancer susceptibility protein-1 ; CDKI ; cyclin-dependent kinase inhibitor ; DAF-DA ; 4 ; 5-diaminofluorescein diacetate ; Cdk ; cyclin-
• 刊名：Nitric Oxide
• 出版年：2012
• 期刊代码：181_10898603
• 类别：bio
• 出版时间：31 March, 2012
• 卷：26
• 期：3
• 页码：182-191
• 文件大小：1293 K

摘要

Nitric oxide (NO) works as a bi-modal effector of cell proliferation, inducing either the increase or decrease of cell growth when cells are exposed, respectively, to low or high NO concentrations. To get further insight into the action of NO, we tested the effect of short- and long-lived NO donors on the control of the cell cycle in human neuroblastoma NB69 cells. We demonstrated that long-time exposure of cells to NO not only decreased the expression and/or the phosphorylation of elements involved in the control of the G₁/S transition, such as the transcriptional repressor pRb and cyclin D1, but also down-regulated systems controlling the S and G₂/M phases, such as the phosphorylation of Cdk1(cdc2) and the expression of cyclins A and B1. Increasing concentrations of NO also induced a biphasic effect on the expression of cyclins D1, A and B1, while this effect was less pronounced for cyclin E expression, but the levels of mRNAs of those cyclins changed in a distinct and complex manner. NO also changed the phosphorylation pattern of cyclin E and decreased the levels of phospho-cyclins D1 and B1. Moreover, NO decreased the expression of the Cdk inhibitors p16^Ink4a and p19^Ink4d, without affecting p27^Kip1. In contrast, NO induced a biphasic effect on p21^Cip1/Waf1 expression. The BRCA1/Chk1/p53 pathway mediated the upregulation of p21^Cip1/Waf1. We also demonstrated that the NO-mediated up-regulation of p21^Cip1/Waf1 was inversely correlated with the activation status of the p38MAPK pathway.