Retinoblastoma protein dephosphorylation is an early event of cellular response to prooxidant conditions.
The modification of intracellular redox conditions with diethylmaleate (DEM), a glutathione-depleting agent, induces a p53-independent growth arrest mediated by the accumulation of p21(waf1) mRNA and protein. The same treatment also induces the retinoblastoma protein (pRb) dephosphorylation. This dephosphorylation (i) is very fast, being observed already 5 min after the exposure of the cells to DEM, (ii) is dependent on the prooxidant effects of DEM, being prevented by the treatment with N-acetylcysteine and (iii) is completely reversible, since the rephosphorylation of pRb is promptly obtained upon the removal of the glutathione-depleting agent from the culture medium. The dephosphorylation of pRb is independent of the accumulation of p21(waf1) induced by DEM; in fact, p21(waf1) levels start to increase much later after DEM treatment and accordingly cyclin-dependent kinase activities are not yet induced when pRb is already dephosphorylated following DEM treatment. Finally, pRb dephosphorylation is catalyzed by phosphatases activated by DEM treatment.
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Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, via S. Pansini 5, 80131, Naples, Italy.
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D000111:Acetylcysteine / Q000494:pharmacology; D017502:Adenovirus E2 Proteins / Q000378:metabolism; D019925:Cyclin A / Q000037:antagonists & inhibitors / Q000378:metabolism; D019926:Cyclin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D008298:Maleates / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D013997:Time Factors
D017502:Adenovirus E2 Proteins; C534699:CCNB1 protein, human; C493956:CDKN1A protein, human; D019925:Cyclin A; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008298:Maleates; D016877:Oxidants; D017382:Reactive Oxygen Species; D016160:Retinoblastoma Protein; D018844:Cyclin-Dependent Kinases; D010749:Phosphoprotein Phosphatases; C014476:diethyl maleate; D005978:Glutathione; D000111:Acetylcysteine