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Molecular and Cellular Biology, July 2004, p. 6501-6513, Vol. 24, No. 14
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.14.6501-6513.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Distinct Regions of the Interleukin-7 Receptor Regulate Different Bcl2 Family Members

Qiong Jiang,1 Wen Qing Li,1 Robert R. Hofmeister,1 Howard A. Young,2 David R. Hodge,1 Jonathan R. Keller,1 Annette R. Khaled,1 and Scott K. Durum1*

Laboratory of Molecular Immunoregulation,1 Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702-12012

Received 5 November 2003/ Returned for modification 12 December 2003/ Accepted 27 April 2004

The antiapoptotic function of the interleukin-7 (IL-7) receptor is related to regulation of three members of the Bcl2 family: synthesis of Bcl2, phosphorylation of Bad, and cytosolic retention of Bax. Here we show that, in an IL-7-dependent murine T-cell line, different regions of the IL-7 receptor initiate the signal transduction pathways that regulate these proteins. Both Box1 and Y449 are required to signal Bcl2 synthesis and Bax cytosolic retention. This suggests a sequential model in which Jak1, which binds to Box1, is first activated and then phosphorylates Y449, leading to Bcl2 and Bax regulation, accounting for approximately 90% of the survival function. Phosphorylation of Bad required Box1 but not Y449, suggesting that Jak1 also initiates an additional signaling cascade that accounts for approximately 10% of the survival function. Stat5 was activated from the Y449 site but only partially accounted for the survival signal. Proliferation required both Y449 and Box1. Thymocyte development in vivo showed that deletion of Y449 eliminated 90% of {alpha}ß T-cell development and completely eliminated {gamma}{delta} T-cell development, whereas deleting Box 1 completely eliminated both {alpha}ß and {gamma}{delta} T-cell development. Thus the IL-7 receptor controls at least two distinct pathways, in addition to Stat5, that are required for cell survival.

* Corresponding author. Mailing address: National Cancer Institute, Bldg. 560 Rm 31-71, Frederick, MD 21702-1201. Phone: (301) 846-1545. Fax: (301) 846-6720. E-mail: durums{at}mail.ncifcrf.gov.

Molecular and Cellular Biology, July 2004, p. 6501-6513, Vol. 24, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.14.6501-6513.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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