Defective thymocyte proliferation and IL-2 production in transgenic mice expressing a dominant-negative form of CREB

Nature. 1996 Jan 4;379(6560):81-5. doi: 10.1038/379081a0.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activating Transcription Factors
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Blood Proteins / metabolism
  • Cell Differentiation / physiology
  • Cell Division
  • Cyclic AMP Response Element-Binding Protein / chemistry
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / physiology*
  • DNA / metabolism
  • G1 Phase
  • Interleukin-2 / biosynthesis*
  • Lymphocyte Activation
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation
  • Phosphorylation
  • Receptors, Antigen, T-Cell / metabolism
  • Regulatory Sequences, Nucleic Acid
  • Serine / metabolism
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology
  • Thymus Gland / cytology*
  • Transcription Factors / metabolism


  • Activating Transcription Factors
  • Blood Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Interleukin-2
  • Receptors, Antigen, T-Cell
  • Transcription Factors
  • Serine
  • DNA