The threshold pattern of calcineurin-dependent gene expression is altered by loss of the endogenous inhibitor calcipressin.
Calcineurin links calcium signaling to transcriptional responses in the immune, nervous and cardiovascular systems. To determine the function of the calcipressins, a family of putative calcineurin inhibitors, we assessed the calcineurin-dependent process of T cell activation in mice engineered to lack the gene encoding calcipressin 1 (Csp1). Csp1 regulated calcineurin in vivo, and genes triggered in an immune response had unique transactivation thresholds for T cell receptor stimulation. In the absence of Csp1, the apparent transactivation thresholds for all these genes were shifted because of enhanced calcineurin activity. This unbridled calcineurin activity drove Fas ligand expression, which normally requires high T cell receptor stimulation and results in the premature death of T helper type 1 cells. Thus, calcipressins modulate the pattern of calcineurin-dependent transcription, and may influence calcineurin activity beyond calcium to integrate a broad array of signals into the cellular response.
Ryeom
Sandra
S
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
Greenwald
Rebecca J
RJ
Sharpe
Arlene H
AH
McKeon
Frank
F
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019703:Calcineurin / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000276:immunology* / Q000494:pharmacology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010766:Phosphorylation; D011506:Proteins; D018417:Th1 Cells / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology; D015533:Transcriptional Activation / Q000276:immunology
D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; C486303:Dscr1l1 protein, mouse; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011506:Proteins; C108612:RCAN1 protein, human; D014157:Transcription Factors; D007371:Interferon-gamma; D019703:Calcineurin; D002118:Calcium