Apoptosis of T Cells Mediated by Ca ²⁺ -Induced Release of the Transcription Factor MEF2

Abstract

T cell receptor (TCR)-induced apoptosis of thymocytes is mediated by calcium-dependent expression of the steroid receptors Nur77 and Nor1. Nur77 expression is controlled by the transcription factor myocyte enhancer factor 2 (MEF2), but how MEF2 is activated by calcium signaling is still obscure. Cabin1, a calcineurin inhibitor, was found to regulate MEF2. MEF2 was normally sequestered by Cabin1 in a transcriptionally inactive state. TCR engagement led to an increase in intracellular calcium concentration and the dissociation of MEF2 from Cabin1, as a result of competitive binding of activated calmodulin to Cabin1. The interplay between Cabin1, MEF2, and calmodulin defines a distinct signaling pathway from the TCR to the Nur77 promoter during T cell apoptosis.

Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

“…MEF2 is a transcription factor that has been shown to be activated by p38 MAP kinase through phosphorylation (Yang et al, 1999;Zhao et al, 1999aZhao et al, , 2000aHan and Molkentin, 2000). MEF2 is reported to regulate the transcription of the orphan receptor TR3 (nur77) (Youn et al, 1999Kasler et al, 2000;Liu et al, 2001). We have found that there is a direct link between the activation of MEK and subsequent activation of p38 with the phosphorylation of MEF2 (Holmes et al, 2003b).…”

Class II histone deacetylases: versatile regulators

“…3) [25,74,76,77]. Activation of T-cell receptors disrupts the interaction of MEF2-D with HDAC4 and Cabin-1, most probably through a Ca 2þ signal and CaM activation.…”

MEF2C is required for the normal allocation of cells between the ventricular and sinoatrial precursors of the primary heart field

“…One of the factors whose genetic ablation causes morphological and transcriptional abnormalities during early cardiogenesis is MEF2C. It is a member of the small MEF2 family of MADS-box containing transcription factors that have been implicated in several fundamental processes including myogenesis, fibertype specification, cardiac hypertrophy, atherosclerosis, and as both an activator and inhibitor of apoptosis (Molkentin et al, 1995;Woronicz et al, 1995;Firulli et al, 1996;Kolodziejczyk et al, 1999;Mao et al, 1999;Youn et al, 1999;Okamoto et al, 2000;Passier et al, 2000;Wu et al, 2000;Dunn et al, 2001;Yan et al, 2001). Deletion of the mef2c gene results in a heart with a small, nonlooping LV, loss of the RV, no trabeculation, and decreased expression of several cardiac-specific genes (Lin et al, , 1998Bi et al, 1999;Bruneau et al, 2000;Liu et al, 2001).…”