title: Involvement of RB kinases and phosphatases in life and death decisions.
abstract: Previously we found that retinoblastoma protein (RB) became dephosphorylated in an early stage of DNA damage-induced, p53-independent apoptosis. Here, we report that both RB dephosphorylation and apoptosis are regulated by relative levels of RB kinases (cyclin-dependent kinases, or cdks) and phosphatases. Treatment of human Jurkat T cells with roscovitine, a potent and selective synthetic inhibitor of several cdks, rapidly induced RB dephosphorylation, which was followed by induction of apoptosis-associated internucleosomal DNA fragmentation. The roscovitine treatment did not increase levels of the endogenous cdk inhibitor proteins p16(Ink4a), p27(kip1) and p21(Waf1), supporting the idea that the observed RB dephosphorylation was due to a direct inhibition of cdk activities by roscovitine. Treatment with a protein kinase C inhibitor (sphingosine or staurosporine), which leads to suppression of several cdk kinase activities, also induced cellular RB dephosphorylation and apoptosis. Finally, roscovitine- or sphingosine-induced RB dephosphorylation was blocked by a specific inhibitor of protein-serine/threonine phosphatases (calyculin A or okadaic acid). Therefore, RB phosphorylation status and cellular fate are regulated by the ratio of RB kinases to RB phosphatases.
authors: UNIV PITTSBURGH,SCH MED,DEPT PHARMACOL,PITTSBURGH,PA 15213. UNIV PITTSBURGH,INST CANC,PITTSBURGH,PA 15213. CNRS,BIOL STN,F-29682 ROSCOFF,FRANCE.
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authors: An
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authors: Dineley
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authors: Zhang
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authors: Termin
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authors: Meijer
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authors: Dou