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

Brennan, Paul ORCID: https://orcid.org/0000-0001-8792-0499, Babbage, J. W., Thomas, G. and Cantrell, D. 1999. p70s6k integrates phosphatidylinositol 3-Kinase and rapamycin-regulated signals for E2F regulation in T lymphocytes. Molecular and Cellular Biology 19 (7) , pp. 4729-4738.

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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 p70(s6k), 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 p70(s6k) 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 p70(s6k) 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 p70(s6k) 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 p70(s6k) 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 p70(s6k) that regulates a crucial G1 checkpoint in T lymphocytes.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	American Society for Microbiology
ISSN:	0270-7306
Last Modified:	25 Oct 2022 09:08
URI:	https://orca.cardiff.ac.uk/id/eprint/57329

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