p38 and extracellular signal-regulated kinases regulate the myogenic program at multiple steps
| Autor: | James R. Feramisco, Kumiko Tamura, Fang Wen, Kunjan S Bhakta, Pamela J. Woodring, Pier Lorenzo Puri, Jean Y. J. Wang, Zhenguo Wu, Michael Karin |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Mef2
Transcription Genetic E-box MADS Domain Proteins Biology MyoD p38 Mitogen-Activated Protein Kinases Cell Line Mice Phosphatidylinositol 3-Kinases MyoD Protein Animals Humans Insulin-Like Growth Factor I Phosphorylation Molecular Biology Cell Growth and Development Myogenin Cells Cultured Myogenesis MEF2 Transcription Factors Cell Differentiation Cell Biology Molecular biology Cell biology DNA-Binding Proteins Enzyme Activation Isoenzymes Myogenic Regulatory Factors Myogenic regulatory factors MYF5 Mitogen-Activated Protein Kinases Signal Transduction Transcription Factors |
| Zdroj: | Molecular and cellular biology. 20(11) |
| ISSN: | 0270-7306 |
| Popis: | 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 family (7). The MEF2 proteins (MEF2A, MEF2B, MEF2C, and MEF2D) form homo- or heterodimers which bind to a consensus AT-rich sequence (MEF2 site), found in the promoters of many muscle-specific genes. Myogenic bHLH and MEF2 cooperate to synergistically activate muscle-specific transcription through interactions mediated by the basic region and the MADS domain, respectively (44, 45). The study of muscle differentiation has benefited from the availability of several myogenic cell lines which allow biochemical dissection of the myogenic pathway. These myogenic cell lines (e.g., mouse C2C12 and rat L6) can be induced to differentiate by withdrawal of mitogens, such as serum. Many negative regulators of myogenesis (e.g., Id, Twist, oncogenic Ras, and the viral proteins E1A and simian virus 40 T antigen) have been identified (1, 34). However, little is known about the intracellular components that positively regulate the activities of myogenic transcription factors, especially those that are involved in receiving and transducing extracellular cues. One extracellular signal that positively regulates myogenesis is insulin-like growth factor (IGF). IGF activates the phosphatidylinositol-3 kinase (PI3K) signaling pathway, which is required for myogenesis (11, 29, 30). However, how this signaling pathway influences myogenic transcription remains to be defined. In eukaryotic cells, mitogen-activated protein kinases (MAPKs) are components of several important signaling pathways that relay extracellular cues to transcription factors in the nucleus (24, 25, 32, 41, 51). For mammals, three MAPK pathways, including the extracellular signal-regulated kinases (ERK1 and -2), the Jun–N-terminal kinases (JNK1, -2, and -3), and the p38 isoforms (α, β, γ, and δ) have been characterized (references 51 and 43 and references therein). In general, each group of MAPKs is activated by two homologous MAPK kinases (MKKs [also called MAPKKs]), including MEK1 and -2 for the ERKs, JNK kinase 1 and 2 (JNKK1 and -2) (or MKK4 and -7) for the JNKs, and MKK3 and -6 for the p38s (26, 51). Except for JNKK1, which can also activate p38 in vitro (14, 38), all other MKKs specifically activate their MAPK targets and have little activity on members of other groups. The ERK pathway has been implicated in the control of muscle differentiation, although its role remains controversial, with some reports suggesting a positive function (5, 11) and others suggesting a negative function (18). p38 has also been reported to activate certain MEF2 family members (21, 40, 48, 61, 67) and to stimulate muscle differentiation (12, 64). However, the upstream signals which regulate p38 activation at the onset of muscle differentiation and the mechanism(s) by which p38 activates myogenic transcription remain elusive. Using a combination of different approaches, we found that the p38 kinase is rapidly activated in muscle cells induced to differentiate by serum withdrawal, through a pathway distinct from that activated in response to stress and cytokines. Specific inhibition of p38 prevents differentiation of both established muscle cell lines and human primary myoblasts, while deliberate p38 activation stimulates muscle-specific reporters, accelerates myotube formation, and induces the expression of myogenic markers despite the presence of serum, which otherwise inhibits muscle differentiation. p38 exerts its stimulatory effect on myogenesis by enhancing the transcriptional activities of both MyoD and MEF2A and -C through distinct mechanisms. While MEF2 proteins are activated by direct phosphorylation of residues located within the activation domain, p38-mediated activation of MyoD is likely to occur by an indirect mechanism. The p38 pathway is activated independently of the IGF-PI3K pathway, although the integrity of both these pathways is required to stimulate muscle differentiation. Conversely, the ERK pathway plays a dual role during myogenic differentiation, being inhibitory at early stages and stimulatory at late stages. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|