p66SHC Promotes Apoptosis and Antagonizes Mitogenic Signaling in T Cells

Abstract

Of the three Shc isoforms, p66Shc is responsible for fine-tuning p52/p46Shc signaling to Ras and has been implicated in apoptotic responses to oxidative stress. Here we show that human peripheral blood lymphocytes and mouse thymocytes and splenic T cells acquire the capacity to express p66Shc in response to apoptogenic stimulation. Using a panel of T-cell transfectants and p66Shc^−/− T cells, we show that p66Shc expression results in increased susceptibility to apoptogenic stimuli, which depends on Ser36 phosphorylation and correlates with an altered balance in apoptosis-regulating gene expression. Furthermore, p66Shc blunts mitogenic responses to T-cell receptor engagement, at least in part by transdominant inhibition of p52Shc signaling to Ras/mitogen-activated protein kinases, in an S36-dependent manner. The data highlight a novel interplay between p66Shc and p52Shc in the control of T-cell fate.

SUPPLEMENTAL MATERIAL

We thank Gary Koretzky for the generous gift of the FasL reporter construct, Makio Iwashima for his kind gift of JSL1 cells, Mario Milco D'Elios for providing buffy coats and valuable input, Silvia Valensin for advice on the flow cytometric analysis of mouse T cells, Susanna Pennacchini, Alfredo Pezzicoli, and Mariateresa Savino for their generous help, and Emanuele Orsini for his assistance with the mice. We are indebted to Paolo Bernardi, Valeria Petronilli, and John L. Telford for productive discussions and critical reading of the manuscript. The technical assistance of Sonia Grassini and secretarial assistance of Giancarlo Benocci are gratefully acknowledged.

This work was generously supported by the Italian Association for Cancer Research. The support of the Consiglio Nazionale delle Ricerche, Telethon (grant E.1161) and the University of Siena is also gratefully acknowledged. S.P. and C.U. are recipients of a FIRC fellowship.