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• W1509038923 endingPage "22" @default.
• W1509038923 startingPage "7410" @default.
• W1509038923 abstract "Transformed cells are selectively sensitized to apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol after their recruitment to S phase. During S phase, cyclin A-dependent kinase activity neutralizes E2F-1 allowing orderly S phase progression. Inhibition of cyclin A-dependent kinase by flavopiridol could cause inappropriately persistent E2F-1 activity during S phase traversal and exit. Transformed cells, with high baseline levels of E2F-1 activity, may be particularly sensitive to cyclin A-dependent kinase inhibition, as the residual level of E2F-1 activity that persists may be sufficient to induce apoptosis. Here, we demonstrate that flavopiridol treatment during S phase traversal results in persistent expression of E2F-1. The phosphorylation of E2F-1 is markedly diminished, whereas that of the retinoblastoma protein is minimally affected, so that E2F-1/DP-1 heterodimers remain bound to DNA. In addition, manipulation of E2F-1 levels leads to predictable outcomes when cells are exposed to flavopiridol during S phase. Tumor cells expressing high levels of ectopic E2F-1 are more sensitive to flavopiridol-induced apoptosis during S phase compared with parental counterparts, and high levels of ectopic E2F-1 expression are sufficient to sensitize nontransformed cells to flavopiridol. Furthermore, E2F-1 activity is required for flavopiridol-induced apoptosis during S phase, which is severely compromised in cells homozygous for a nonfunctional E2F-1 allele. Finally, the response to flavopiridol during S phase is blunted in cells expressing a nonphosphorylatable E2F-1 mutant incapable of binding cyclin A, suggesting that the modulation of E2F-1 activity produced by flavopiridol-mediated cyclin-dependent kinase inhibition is critical for the apoptotic response of S phase cells." @default.
• W1509038923 created "2016-06-24" @default.
• W1509038923 creator A5014268033 @default.
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• W1509038923 creator A5048641551 @default.
• W1509038923 creator A5056591893 @default.
• W1509038923 creator A5075376877 @default.
• W1509038923 date "2003-11-01" @default.
• W1509038923 modified "2023-10-16" @default.
• W1509038923 title "Flavopiridol-induced apoptosis during S phase requires E2F-1 and inhibition of cyclin A-dependent kinase activity." @default.
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• W1509038923 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/14612540" @default.
• W1509038923 hasPublicationYear "2003" @default.
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