p70s6k integrates phosphatidylinositol 3-kinase and rapamycin- regulated signals for E2F regulation in T lymphocytes

Paul Brennan, J. W. Babbage, G. Thomas, Doreen Cantrell (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

112 Citations (Scopus)

Abstract

In T lymphocytes, the hematopoietic cytokine interleukin-2 (IL-2) uses phosphatidylinositol 3-kinase (PI 3-kinase)-induced signaling pathways to regulate E2F transcriptional activity, a critical cell cycle checkpoint. PI 3-kinase also regulates the activity of p70s6k, the 40S ribosomal protein S6 kinase, a response that is abrogated by the macrolide rapamycin. This immunosuppressive drug is known to prevent T-cell proliferation, but the precise point at which rapamycin regulates T-cell cycle progression has yet to be elucidated. Moreover, the effects of rapamycin on, and the role of p70s6k in, IL-2 and PI 3-kinase activation of E2Fs have not been characterized. Our present results show that IL-2- and PI 3-kinase-induced pathways for the regulation of E2F transcriptional activity include both rapamycin-resistant and rapamycin-sensitive components. Expression of a rapamycin-resistant mutant of p70s6k in T cells could restore rapamycin- suppressed E2F responses. Thus, the rapamycin-controlled processes involved in E2F regulation appear to be mediated by p70(s6k). However, the rapamycin- resistant p70s6k could not rescue rapamycin inhibition of T-cell cycle entry, consistent with the involvement of additional, rapamycin-sensitive pathways in the control of T-cell cycle progression. The present results thus show that p70s6k is able to regulate E2F transcriptional activity and provide direct evidence for the first time for a link between IL-2 receptors, PI 3-kinase, and p70s6k that regulates a crucial G1 checkpoint in T lymphocytes.

Original languageEnglish
Pages (from-to)4729-4738
Number of pages10
JournalMolecular and Cellular Biology
Volume19
Issue number7
DOIs
Publication statusPublished - Jul 1999

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