Bcl-2- and CrmA-inhibitable dephosphorylation and cleavage of retinoblastoma protein during etoposide-induced apoptosis.
Cell numbers are regulated by a balance between proliferation and apoptosis (programmed cell death). Recent evidence suggests that proteins regulating cell proliferation also mediate apoptosis. Therefore, cellular fate might be determined by cross talk between regulators of cell cycle progression and apoptosis. Previously, we had found that during DNA damage-induced apoptosis, retinoblastoma protein (RB), an important G1/S regulator and tumor suppressor, became dephosphorylated and then immediately cleaved into p48 and p68 fragments. Here, we report that expression of the Bcl-2 oncoprotein, an inhibitor of caspases (interleukin 1 -converting enzyme-like proteases), blocked RB dephosphorylation, RB cleavage and apoptosis in etoposide-treated human Jurkat T cells. In addition, expression of the cowpox virus CrmA protein, a direct inhibitor of caspases, also inhibited both RB changes and apoptosis. Taken together, our findings demonstrate important roles for caspases in the processes of etoposide-induced RB dephosphorylation, RB proteolysis and apoptosis.
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Department of Pharmacology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213-2582, USA.
Johnson
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Jin
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Antoku
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Dou
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QP
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015843:Serpins / Q000096:biosynthesis*; D014764:Viral Proteins
D019384:Nucleic Acid Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; D015843:Serpins; D014764:Viral Proteins; D005047:Etoposide; C074641:interleukin-1beta-converting enzyme inhibitor; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases