Deletion of calcineurin and myocyte enhancer factor 2 (MEF2) binding domain of Cabin1 results in enhanced cytokine gene expression in T cells.
Cabin1 binds calcineurin and myocyte enhancer factor 2 (MEF2) through its COOH-terminal region. In cell lines, these interactions were shown to inhibit calcineurin activity after T cell receptor (TCR) signaling and transcriptional activation of Nur77 by MEF2. The role of these interactions under physiological conditions was investigated using a mutant mouse strain that expresses a truncated Cabin1 lacking the COOH-terminal calcineurin and MEF2 binding domains. T and B cell development and thymocyte apoptosis were normal in mutant mice. In response to anti-CD3 stimulation, however, mutant T cells expressed significantly higher levels of interleukin (IL)-2, IL-4, IL-9, IL-13, and interferon gamma than wild-type T cells. The enhanced cytokine gene expression was not associated with change in nuclear factor of activated T cells (NF-AT)c or NF-ATp nuclear translocation but was preceded by the induction of a phosphorylated form of MEF2D in mutant T cells. Consistent with the enhanced cytokine expression, mutant mice had elevated levels of serum immunoglobulin (Ig)G1, IgG2b, and IgE and produced more IgG1 in response to a T cell-dependent antigen. These findings suggest that the calcineurin and MEF2 binding domain of Cabin1 is dispensable for thymocyte development and apoptosis, but is required for proper regulation of T cell cytokine expression probably through modulation of MEF2 activity.
Esau
C
C
Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, 40 Ames St., Cambridge, MA 02139, USA.
Boes
M
M
Youn
H D
HD
Tatterson
L
L
Liu
J O
JO
Chen
J
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000502:physiology; D001665:Binding Sites; D019703:Calcineurin / Q000737:chemistry / Q000502:physiology*; D016207:Cytokines / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000502:physiology*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000145:classification; D047908:Intracellular Signaling Peptides and Proteins; D064326:MEF2 Transcription Factors; D051379:Mice; D018006:Myogenic Regulatory Factors; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000737:chemistry / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C113151:Cabin1 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D064326:MEF2 Transcription Factors; C578044:Mef2d protein, mouse; D018006:Myogenic Regulatory Factors; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D019703:Calcineurin