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Molecular and Cellular Biology, July 1999, p. 4729-4738, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

p70s6k Integrates Phosphatidylinositol 3-Kinase and Rapamycin-Regulated Signals for E2F Regulation in T Lymphocytes

Paul Brennan,1 J. W. Babbage,1 G. Thomas,2 and Doreen Cantrell1,*

Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom,1 and Friedrich Miescher Institute, CH-4002 Basel, Switzerland2

Received 14 September 1998/Returned for modification 16 November 1998/Accepted 22 April 1999

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 p70s6k. 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.

* Corresponding author. Mailing address: Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, Room 105, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. Phone: 44 171 269 3307. Fax: 44 171 269 2831. E-mail: cantrell{at}icrf.icnet.uk.

Molecular and Cellular Biology, July 1999, p. 4729-4738, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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