The extracellular signals which regulate the myogenic program are transduced to the nucleus by mitogenactivated protein kinases (MAPKs). We have investigated the role of two MAPKs, p38 and extracellular signal-regulated kinase (ERK), whose activities undergo significant changes during muscle differentiation. p38 is rapidly activated in myocytes induced to differentiate. This activation differs from those triggered by stress and cytokines, because it is not linked to Jun-N-terminal kinase stimulation and is maintained during the whole process of myotube formation. Moreover, p38 activation is independent of a parallel promyogenic pathway stimulated by insulin-like growth factor 1. Inhibition of p38 prevents the differentiation program in myogenic cell lines and human primary myocytes. Conversely, deliberate activation of endogenous p38 stimulates muscle differentiation even in the presence of antimyogenic cues. Much evidence indicates that p38 is an activator of MyoD: (i) p38 kinase activity is required for the expression of MyoD-responsive genes, (ii) enforced induction of p38 stimulates the transcriptional activity of a Gal4-MyoD fusion protein and allows efficient activation of chromatin-integrated reporters by MyoD, and (iii) MyoD-dependent myogenic conversion is reduced in mouse embryonic fibroblasts derived from p38␣ ؊/؊ embryos. Activation of p38 also enhances the transcriptional activities of myocyte enhancer binding factor 2A (MEF2A) and MEF2C by direct phosphorylation. With MEF2C, selective phosphorylation of one residue (Thr293) is a tissue-specific activating signal in differentiating myocytes. Finally, ERK shows a biphasic activation profile, with peaks of activity in undifferentiated myoblasts and postmitotic myotubes. Importantly, activation of ERK is inhibitory toward myogenic transcription in myoblasts but contributes to the activation of myogenic transcription and regulates postmitotic responses (i.e., hypertrophic growth) in myotubes.In the past decade, much has been learned about the molecular mechanisms that govern myogenesis owing mainly to the discovery of two groups of myogenic transcription factors (4,45,62). The first group includes the myogenic regulatory factors (MRFs), which belong to the basic helix-loop-helix (bHLH) protein family. This MRF group consists of four members: Myf5, MyoD, myogenin, and MRF4, all of which are specifically expressed in skeletal muscles. One of the unique features of these MRFs is that when they are ectopically expressed in fibroblasts or certain other nonmuscle cells, each has the ability to initiate the myogenic program and convert nonmuscle cells to myogenic derivatives (9, 59). Myogenic bHLH proteins heterodimerize with other ubiquitous bHLH proteins (like the E2A gene products, E12, and E47) to efficiently bind a consensus DNA site: CANNTG (also called the E box) (4, 33). The second group of transcription factors important in muscle differentiation consists of four different myocyte enhancer binding factor 2 (MEF2) proteins, which belong to the MADS box...

The F-actin cytoskeleton is a fundamental component of all eukaryotic cells. It provides force and stability and plays an integral role in a diverse array of cellular processes. The spatiotemporal regulation of F-actin dynamics is essential for proper biological output. The basic molecular machinery underlying the assembly and disassembly of filamentous actin is conserved in all eukaryotic cells. Additionally, protein tyrosine kinases, found only in multicellular eukaryotes, provide links between extracellular signals and F-actin-dependent cellular processes. Among the tyrosine kinases, c-Abl and its relative Arg are unique in binding directly to F-actin. Recent results have demonstrated a role for c-Abl in membrane ruffling, cell spreading, cell migration, and neurite extension in response to growth factor and extracellular matrix signals. c-Abl appears to regulate the assembly of F-actin polymers into different structures, depending on the extracellular signal. Interestingly, c-Abl contains nuclear import and export signals, and the nuclear c-Abl inhibits differentiation and promotes apoptosis in response to genotoxic stress. The modular structure and the nuclear-cytoplasmic shuttling of c-Abl suggest that it integrates multiple signals to coordinate F-actin dynamics with the cellular decision to differentiate or to die.

The nonreceptor tyrosine kinase encoded by the c-Abl gene has the unique feature of an F-actin binding domain (FABD). Purified c-Abl tyrosine kinase is inhibited by F-actin, and this inhibition can be relieved through mutation of its FABD. The c-Abl kinase is activated by physiological signals that also regulate the actin cytoskeleton. We show here that c-Abl stimulated the formation of actin microspikes in fibroblasts spreading on fibronectin. This function of c-Abl is dependent on kinase activity and is not shared by c-Src tyrosine kinase. The Abl-dependent F-actin microspikes occurred under conditions where the Rho-family GTPases were inhibited. The FABD-mutated c-Abl, which is active in detached fibroblasts, stimulated F-actin microspikes independent of cell attachment. Moreover, FABD-mutated c-Abl stimulated the formation of F-actin branches in neurites of rat embryonic cortical neurons. The reciprocal regulation between F-actin and the c-Abl tyrosine kinase may provide a self-limiting mechanism in the control of actin cytoskeleton dynamics.

The catalytic activity of c-Abl tyrosine kinase is reduced in fibroblasts that are detached from the extracellular matrix. We report here that a deletion of the extreme C terminus of c-Abl (

Several transcriptional coactivators have been implicated in modulating the transcriptional activities of nuclear hormone receptors in vitro. Potential roles of these cofactors in important physiological processes such as energy homeostasis remain unknown. We report here that a developmental arrest in interscapular brown fat and defective adaptive thermogenesis occur in mice lacking both the p160 family transcriptional coactivators SRC-1 and p/CIP due to a failure in induction of selective PPARgamma target genes involved in adipogenesis and mitochondrial uncoupling. In the absence of p/CIP and SRC-1, mice eat more food on both regular chow and a high-fat diet because of decreased blood leptin levels. However, the p/CIP(-/-)/SRC-1(-/-) mice are lean and resistant to high-fat-diet-induced obesity. They exhibit increased basal metabolic rates and heightened levels of physical activity. Therefore, p/CIP and SRC-1 play critical roles in energy balance by controlling both energy intake and energy expenditure.