The process by which T cells are activated, and the consequences of activation (e.g. new gene transcription, cytokine production, apoptosis), are being investigated by a variety of approaches: 1) Inhibitors of proteasome activity block thymocyte apoptosis. We have found that IAPs (inhibitors of apoptosis) are selectively degraded in proteasomes in response to apoptotic stimuli. The IAPs themselves have ubiquitin protein ligase (E3) activity, and are responsible for their own ubiquitination. The dynamic regulation of E3 activity is currently the subject of investigation. 2) The TNF receptors are associated with two members of the IAP family (c-IAP1 and c-IAP2) as well as adaptor molecules such as TRAF2, which are necessary for signal transduction. We have found that upon TNF signaling TRAF2 is selectively ubiquitinated and degraded in proteasomes. How this is regulated in vivo, and the biological consequences thereof, is under investigation. 3) Glucocorticoids are immunosuppressive, largely because they interfere with the transcription of many activation-induced genes, a phenomenon that is thought to be due largely to direct binding of the liganded glucocorticoid receptor. We have found that a glucocorticoid-induced gene, GILZ, is able to attenuate TCR signaling events by directly binding to and interfering with the action of AP-1, providing an alternative mechanism for glucocorticoid-induced immunosuppression.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009290-18
Application #
6950564
Study Section
(LICB)
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2003
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Ashwell, Jonathan D (2006) The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat Rev Immunol 6:532-40
Schito, Marco L; Demidov, Oleg N; Saito, Shin'ichi et al. (2006) Wip1 phosphatase-deficient mice exhibit defective T cell maturation due to sustained p53 activation. J Immunol 176:4818-25
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Mittelstadt, Paul R; Ashwell, Jonathan D (2003) Disruption of glucocorticoid receptor exon 2 yields a ligand-responsive C-terminal fragment that regulates gene expression. Mol Endocrinol 17:1534-42
Rengarajan, J; Mittelstadt, P R; Mages, H W et al. (2000) Sequential involvement of NFAT and Egr transcription factors in FasL regulation. Immunity 12:293-300

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