Myocyte enhancer factor-2 (MEF2) transcription factors control muscle-specific and growth factor-inducible genes. We show that hypertrophic growth of cardiomyocytes in response to phenylephrine and serum is accompanied by activation of MEF2 through a posttranslational mechanism mediated by calcium, calmodulindependent protein kinase (CaMK), and mitogen-activated protein kinase (MAPK) signaling. CaMK stimulates MEF2 activity by dissociating class II histone deacetylases (HDACs) from the DNA-binding domain. MAPKs, which activate MEF2 by phosphorylation of the transcription activation domain, maximally stimulate MEF2 activity only when repression by HDACs is relieved by CaMK signaling to the DNA-binding domain. These findings identify MEF2 as an endpoint for hypertrophic stimuli in cardiomyocytes and demonstrate that MEF2 mediates synergistic transcriptional responses to the CaMK and MAPK signaling pathways by signal-dependent dissociation from HDACs.M yocyte enhancer factor-2 (MEF2) transcription factors (1) participate in diverse gene regulatory programs, including those for muscle and neural differentiation, cardiac morphogenesis, blood vessel formation, and growth factor responsiveness (reviewed in ref.2). The four MEF2 factors, MEF2A, -B, -C, and -D, share high homology in an amino-terminal MADS (MCMI, Agamous, Deficiens, Serum response factor) domain that mediates DNA-binding and dimerization and an adjacent MEF2-specific domain that influences DNA-binding affinity and interaction with transcriptional cofactors (2). The carboxyl-terminal regions of MEF2 factors, which are more divergent, act as transcription activation domains (TADs).Studies in T cells and fibroblasts have shown that the mitogenactivated protein kinases (MAPKs) p38 and ERK5 stimulate transcriptional activity of MEF2 factors by phosphorylating conserved sites in their TADs (3-12). Calcium, calmodulindependent protein kinase (CaMK), and calcineurin also stimulate MEF2 activity (13,14), but the underlying mechanisms are unknown. It is also unclear whether MAPK, CaMK, and calcineurin pathways cross-talk or act in parallel to activate MEF2.Most studies of MEF2 activation by extracellular signaling have focused on cells that are highly responsive to mitogens. Whether MEF2 retains the ability to respond to growth factor signals in terminally differentiated muscle cells, which are permanently postmitotic, and whether MEF2 is activated in muscle cells by the same signaling pathways as in other cell types has not been determined. In cardiac myocytes, growth factor signals evoke a hypertrophic response characterized by cell enlargement, activation of immediate early genes, reactivation of fetal cardiac muscle genes, and sarcomere assembly (reviewed in ref. 15).To investigate the mechanisms that regulate MEF2 activity in response to extracellular signals and to test whether MEF2 retains its ability to respond to growth factor signals in terminally differentiated muscle cells, we sought to determine whether MEF2 could be activated by hypertrophic signals ...
Signaling events controlled by calcineurin promote cardiac hypertrophy, but the degree to which such pathways are required to transduce the effects of various hypertrophic stimuli remains uncertain. In particular, the administration of immunosuppressive drugs that inhibit calcineurin has inconsistent effects in blocking cardiac hypertrophy in various animal models. As an alternative approach to inhibiting calcineurin in the hearts of intact animals, transgenic mice were engineered to overexpress a human cDNA encoding the calcineurin-binding protein, myocyte-enriched calcineurin-interacting protein-1 (hMCIP1) under control of the cardiac-specific, ␣-myosin heavy chain promoter (␣-MHC). In unstressed mice, forced expression of hMCIP1 resulted in a 5-10% decline in cardiac mass relative to wild-type littermates, but otherwise produced no apparent structural or functional abnormalities. However, cardiac-specific expression of hMCIP1 inhibited cardiac hypertrophy, reinduction of fetal gene expression, and progression to dilated cardiomyopathy that otherwise result from expression of a constitutively active form of calcineurin. Expression of the hMCIP1 transgene also inhibited hypertrophic responses to -adrenergic receptor stimulation or exercise training. These results demonstrate that levels of hMCIP1 producing no apparent deleterious effects in cells of the normal heart are sufficient to inhibit several forms of cardiac hypertrophy, and suggest an important role for calcineurin signaling in diverse forms of cardiac hypertrophy. The future development of measures to increase expression or activity of MCIP proteins selectively within the heart may have clinical value for prevention of heart failure.
Mitogen-activated protein kinase (MAPK) pathways couple intrinsic and extrinsic signals to hypertrophic growth of cardiomyocytes. The MAPK kinase MEK5 activates the MAPK ERK5. To investigate the potential involvement of MEK5±ERK5 in cardiac hypertrophy, we expressed constitutively active and dominant-negative forms of MEK5 in cardiomyocytes in vitro. MEK5 induced a form of hypertrophy in which cardiomyocytes acquired an elongated morphology and sarcomeres were assembled in a serial manner. The cytokine leukemia inhibitory factor (LIF), which stimulates MEK5 activity, evoked a similar response. Moreover, a dominant-negative MEK5 mutant speci®cally blocked LIF-induced elongation of cardiomyocytes and reduced expression of fetal cardiac genes without blocking other aspects of LIFinduced hypertrophy. Consistent with the ability of MEK5 to induce serial assembly of sarcomeres in vitro, cardiac-speci®c expression of activated MEK5 in transgenic mice resulted in eccentric cardiac hypertrophy that progressed to dilated cardiomyopathy and sudden death. These ®ndings reveal a speci®c role for MEK5±ERK5 in the induction of eccentric cardiac hypertrophy and in transduction of cytokine signals that regulate serial sarcomere assembly. Keywords: dilated cardiomyopathy/heart/leukemia inhibitory factor/mitogen-activated protein kinase IntroductionCardiac cells do not divide after birth, so both normal growth of the myocardium and stress-induced myocardial remodeling must take place through hypertrophic growth without cell division (MacLellan and Schneider, 2000). Cardiac hypertrophy can occur by an increase in width of myo®brils, resulting in a thickening of the myocardial wall or`concentric hypertrophy', or by an increase in myo®bril length, producing chamber dilation or`eccentric hypertrophy'. These contrasting forms of hypertrophy are coupled to parallel versus serial assembly of sarcomeres, respectively. In the case of normal physiological growth or exercise-induced hypertrophy, concentric and eccentric hypertrophy occur simultaneously and in a balanced manner, enabling the heart to increase pumping capacity in response to increased demand. Disease states that put stress on the heart can also induce hypertrophy; however, depending on the stimulus, either concentric or eccentric hypertrophy may predominate. Although hypertrophy may compensate initially for the additional demands placed on the heart by disease, continued stress almost inevitably results in decompensation and the development of hypertrophic or dilated cardiomyopathy. In order for any form of hypertrophic remodeling to occur, stress stimuli must activate signaling pathways that regulate protein synthesis, sarcomeric assembly and organization, and gene expression (Sugden and Clerk, 1998;Chien, 1999;Nicol et al., 2000).Mitogen-activated protein kinase (MAPK) pathways provide an important connection between external stimuli that activate a wide variety of cell signaling systems and the nucleus. At the core of each MAPK cascade is a threekinase module in which the m...
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