Trends in Biochemical Sciences
ReviewMEF2: a calcium-dependent regulator of cell division, differentiation and death
Section snippets
The MEF2 family of transcription factors
MEF2 was first described as a muscle-enriched transcription factor that bound to an A/T-rich DNA sequence in the control regions of numerous muscle-specific genes (reviewed in Ref. [1]). However, it soon became apparent that MEF2, while highly expressed in muscle cells, was also expressed at high levels in neurons and at lower levels in a wide range of cell types. There are four vertebrate MEF2 genes, MEF2A, -B, -C and -D, which are expressed in distinct, but overlapping, patterns during
Functions of MEF2 in muscle, neurons and immune cells
MEF2 has been studied most extensively in muscle cells (reviewed in Ref. [1]). MEF2 binds directly to the promoters or enhancers of the majority of muscle-specific genes and interacts with members of the MyoD family of basic helix–loop–helix (bHLH) proteins to activate the skeletal muscle differentiation program. Loss-of-function mutations of the murine MEF2C gene and of the Drosophila melanogaster MEF2 gene have demonstrated an essential role for MEF2 in myogenesis and morphogenesis of
Regulation of cell proliferation by MEF2
A large body of evidence implicates MEF2 as a key downstream effector of mitogenic signaling pathways. The connection between MEF2 and cell proliferation was made with the discovery that MEF2 regulates serum-inducible expression of c-jun, which positively regulates cell-cycle progression [14]. MEF2 has since been shown to play a role in the induction of the c-jun promoter in response to signals emanating from multiple cell surface receptors, including G-protein-coupled receptors [15], the
CaMK signaling
MEF2 proteins act as integrators of calcium signals, many of which are controlled by the intracellular calcium-binding protein calmodulin. The calcium/calmodulin-dependent protein kinase (CaMK) is a potent activator of MEF2 activity 2, 3, 6, 13. CaMK regulation of MEF2 activity appears to be intimately involved in the stimulation of cardiomyocyte hypertrophy, which is associated with the transcriptional activation of an array of fetal cardiac genes 2, 3. A variety of agonists can evoke a
CaMK signaling to HDACs
There appear to be at least 17 HDACs in humans, which are grouped into three classes (I, II and III) on the basis of their homology with three structurally and biochemically distinct yeast HDACs: Rpd3p, Hda1p and Sir2, respectively (reviewed in Ref. [22]). HDACs -4, -5 and -7 are class II HDACs that interact with the MADS/MEF2 domains of all MEF2 family members through a unique 18-amino acid motif not found in other HDACs (reviewed in Ref. [23]). This interaction does not affect MEF2
Calcineurin signaling to MEF2
Calcineurin is a serine/threonine phosphatase that is activated by the binding of calcium and calmodulin. In contrast to CaMK, which is preferentially activated by transient, high-amplitude calcium spikes, calcineurin responds to sustained, low-amplitude calcium transients. The best-known transcriptional targets for calcineurin are members of the NFAT family of transcription factors, which translocate to the nucleus in response to dephosphorylation by calcineurin (reviewed in Ref. [38]).
Control of MEF2 by Cabin and calmodulin
Recent studies have also identified a more direct role for calmodulin in the control of MEF2 activity. In activated T lymphocytes, calcium-bound calmodulin disrupts interactions between MEF2D and a transcriptional repressor, termed Cabin1, which inhibits MEF2-dependent transcription by recruiting class I HDACs to MEF2 target genes via the mSin3 co-repressor 43, 44 (Fig. 3). Calmodulin associates with the MEF2-binding site on Cabin [43]. Thus, the competition between calmodulin and MEF2 for
MAPK signaling to MEF2
MAPKs couple MEF2 to multiple signaling pathways for cell growth and differentiation. MAPKs are calcium-responsive enzymes that are generally divided into three signaling cascades on the basis of the terminal effector kinase in the pathway: the extracellular signal-regulated protein kinase (ERK), c-jun N-terminal kinase (JNK) and p38 kinase pathways. The p38 and ERK pathways have been shown to stimulate MEF2 activity.
Using p38 as bait in a yeast two-hybrid screen, MEF2C was identified as a
Other signaling systems regulating MEF2
The number of signaling pathways that have been shown to impinge on MEF2 is rapidly growing. For example, SMADs, transcriptional regulators that are activated by transforming growth factor-β signaling, have recently been shown to associate with, and stimulate the activity of, the MEF2 transactivation domain [55]. In addition, phosphoinositide-3-kinase (PI3-K) signaling has recently been implicated in the regulation of MEF2 56, 57. PI3-K is essential for muscle differentiation and is a key
Future questions
It is apparent that MEF2 is a target for many signaling pathways involving calcium. Although the mechanisms for MEF2 activation are beginning to be defined, many important questions remain. Among these is how this transcription factor can govern so many cellular processes that are mutually exclusive. An explanation for this regulatory complexity undoubtedly lies in the different partner proteins for MEF2 that will vary between cell types, and in response to different signals in the same cell
Acknowledgements
We thank J. Page and S. Johnson for editorial assistance and A. Tizenor for graphics. Work in our laboratory is supported by The National Institutes of Health, The Muscular Dystrophy Association, The Robert A. Welch Foundation and The D.W. Reynolds Foundation for Clinical Cardiovascular Research. T.A.M. is a Pfizer Fellow of the Life Sciences Research Foundation.
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