DEFECTIVE THYMOCYTE PROLIFERATION AND IL-2 PRODUCTION IN TRANSGENIC MICE EXPRESSING A DOMINANT-NEGATIVE FORM OF CREB

THE basic/leucine zipper (bZip) transcription factor, CREB, binds to t he CRE element (TGANNTCA)(1-5). The transcriptional activity of CREB r equires phosphorylation of the protein on a serine residue at position 119 (ref. 6). CREs are present in a number of T-cell genes(7,8) but t he precise role of CREB in T-cell differentiation and function was unk nown. Here we show that resting thymocytes contain predominantly unpho sphorylated (inactive) CREB, which is rapidly activated by phosphoryla tion on Ser 119 following thymocyte activation. T-cell development is normal in transgenic mice that express a dominant-negative form of CRE B (CREB(A119), with alanine at position 119) under the control of the T-cell-specific CD2 promoter/enhancer. In contrast, thymocytes and T c ells from these animals display a profound proliferative defect charac terized by markedly decreased interleukin-2 production, G1 cell-cycle arrest and subsequent apoptotic death in response to a number of diffe rent activation signals. This proliferative defect is associated with the markedly reduced induction of c-jun, c-fos, Fra-2 and FosB followi ng activation of the CREB(A119), transgenic thymocytes. We propose tha t T-cell activation leads to the phosphorylation and activation of CRE B, which in turn is required for normal induction of the transcription factor AP1 and subsequent interleukin-2 production and cell-cycle pro gression.