Cyclic adenosine 5 '-monophosphate response element binding protein plays a central proliferation and differentiation role in mediating downstream of the pre-TCR complex in developing thymocytes

Grady, G.C., Mason, S.M., Stephen, J., Zuniga-Pflucker, J.C. and Michie, A.M. (2004) Cyclic adenosine 5 '-monophosphate response element binding protein plays a central proliferation and differentiation role in mediating downstream of the pre-TCR complex in developing thymocytes. Journal of Immunology, 173(3), pp. 1802-1810. (doi: 10.4049/jimmunol.173.3.1802) (PMID:15265911)

Abstract

The roles played by specific transcription factors during the regulation of early T cell development remain largely undefined. Several key genes induced during the primary checkpoint of T cell development, beta-selection, contain cAMP response element sites within their enhancer-promoter region that are regulated by CREB activation. In this study, we show that CREB is constitutively phosphorylated in the thymus, but not the spleen. We also show that CREB is activated downstream of the pre-TCR complex, and that the induction of CREB activity is regulated by protein kinase Calpha- and ERK-MAPK-mediated signals. We addressed the importance of this activation by expressing a naturally occurring inhibitor of CREB, inducible cAMP early repressor in wild-type fetal liver-derived lymphoid progenitor cells, and assessed their developmental potential. Fetal thymic organ cultures reconstituted with cells constitutively expressing inducible cAMP early repressor displayed a delay in generating CD4(+)CD8(+) thymocytes and a decrease in cellularity compared with control fetal thymic organ cultures. Taken together, our studies establish that CREB plays a central role in relaying proliferation and differentiation signals from the pre-TCR complex into the nucleus in developing thymocytes.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Michie, Professor Alison
• Authors: Grady, G.C., Mason, S.M., Stephen, J., Zuniga-Pflucker, J.C., and Michie, A.M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Immunology
• Publisher: American Association of Immunologists
• ISSN: 0022-1767
• ISSN (Online): 1550-6606