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 the CRE element (TGANNTCA). The transcriptional activity of CREB requires phosphorylation of the protein on a serine residue at position 119 (ref. 6). CREs are present in a number of T-cell genes but the precise role of CREB in T-cell differentiation and function was unknown. Here we show that resting thymocytes contain predominantly unphosphorylated (inactive) CREB, which is rapidly activated by phosphorylation on Ser 119 following thymocyte activation. T-cell development is normal in transgenic mice that express a dominant-negative form of CREB (CREBA119, with alanine at position 119) under the control of the T-cell-specific CD2 promoter/enhancer. In contrast, thymocytes and T cells from these animals display a profound proliferative defect characterized by markedly decreased interleukin-2 production, G1 cell-cycle arrest and subsequent apoptotic death in response to a number of different activation signals. This proliferative defect is associated with the markedly reduced induction of c-jun, c-fos, Fra-2 and FosB following activation of the CREBA119 transgenic thymocytes. We propose that T-cell activation leads to the phosphorylation and activation of CREB, which in turn is required for normal induction of the transcription factor AP1 and subsequent interleukin-2 production and cell-cycle progression.
Department of Medicine, University of Chicago, Illinois 60637, USA.
K
K
Barton
N
N
Muthusamy
M
M
Chanyangam
C
C
Fischer
C
C
Clendenin
J M
JM
Leiden
D051696:Activating Transcription Factors; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001798:Blood Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D016193:G1 Phase; D007376:Interleukin-2 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D012694:Serine / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology*; D014157:Transcription Factors / Q000378:metabolism
D051696:Activating Transcription Factors; D001798:Blood Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D012694:Serine; D004247:DNA