Phosphorylation site mutated RB exerts contrasting effects on apoptotic response to different stimuli.
The retinoblastoma tumor-suppressor protein (RB) is an important regulator of cell cycle and apoptosis. RB is phosphorylated by cyclin-dependent protein kinase during cell cycle progression. A phosphorylation site mutated (PSM)-RB has previously been shown to cause G1 arrest and to interfere with S phase progression. In this study, we examined the effect of inducible PSM-RB expression on the apoptotic response to three different death stimuli: doxorubicin (DOXO), staurosporine (STS) and tumor necrosis factor (TNF) in Rat-16 cells. Induced expression of PSM-RB attenuated caspase activation by DOXO as a result of cell cycle arrest. STS has been shown to cause RB-dependent G1 arrest or apoptosis; however, expression of PSM-RB did not prevent caspase activation by STS. Surprisingly, induced expression of PSM-RB stimulated the apoptotic response to TNF in Rat-16 cells, which mostly undergo necrosis in the absence of PSM-RB. These results show that PSM-RB exerts disparate effects on apoptotic response to different stimuli, and that cell cycle arrest does not always associate with resistance to apoptosis.
Masselli
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Division of Hematology-Oncology and Moores Cancer Center, Department of Medicine, UCSD School of Medicine, Health Sciences Drive, University of California San Diego, La Jolla, CA 92093, USA.
Wang
J Y J
JY
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques; D002453:Cell Cycle; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D051381:Rats; D016160:Retinoblastoma Protein / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D016160:Retinoblastoma Protein; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D020169:Caspases; D019311:Staurosporine