Flavopiridol-Induced Apoptosis during S Phase Requires E2F-1 and Inhibition of Cyclin A-Dependent Kinase Activity

Jingrui Jiang, Christian B. Matranga, Dongpo Cai, Vaughan M. Latham, Xinxin Zhang, April M. Lowell, Fabio Martelli, Geoffrey I. Shapiro

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)7410-7422
Number of pages13
JournalCancer Research
Volume63
Issue number21
Publication statusPublished - Nov 1 2003

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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  • Cite this

    Jiang, J., Matranga, C. B., Cai, D., Latham, V. M., Zhang, X., Lowell, A. M., Martelli, F., & Shapiro, G. I. (2003). Flavopiridol-Induced Apoptosis during S Phase Requires E2F-1 and Inhibition of Cyclin A-Dependent Kinase Activity. Cancer Research, 63(21), 7410-7422.