Regulation of C2C12 myogenic terminal differentiation by MKK3/p38α pathway

Abstract

The signal transduction pathways connecting cell surface receptors to the activation of muscle-specific promoters and leading to myogenesis are still largely unknown. Recently, a contribution of the p38 mitogen-activated protein kinase (MAPK) pathway to this process was evoked through the use of pharmacological inhibitors. We used several mutants of the kinases composing this pathway to modulate the activity of the muscle-specific myosin light chain and myogenin promoters in C2C12 cells by transient transfections. In addition, we show for the first time, using a stable C2C12 cell line expressing a dominant-negative form of the p38 activator MAPK kinase (MKK)3, that a functional p38 MAPK pathway is indeed required for terminal muscle cell differentiation. The most obvious phenotype of this cell line, besides the inhibition of the activation of p38, is its inability to undergo terminal differentiation. This phenotype is accompanied by a drastic inhibition of cell cycle and myogenesis markers such as p21, p27, MyoD, and troponin T, as well as a profound disorganization of the cytoskeleton.

Prion and TNFα: TAC(E)it agreement between the prion protein and cell signaling

“…[17][18][19][20] Finally, P-p38 induces p21, an inhibitor of cyclin-dependent kinases, promoting cell cycle arrest and terminal differentiation of muscle precursors. 18,21 Interestingly, we found that the Akt kinase, which works synergistically with p38 in the SWI/SNF-mediated chromatin remodeling, 20,22 was also downregulated in regenerating PrP-KO muscles. That the absence of PrP C delayed withdrawal of muscle precursors from the cell cycle and, hence, retarded their differentiation, was further confirmed by the prolonged remarkable capacity to recover from injury and express substantial PrP C amounts.…”

Comparative Proteomes of the Proliferating C2C12 Myoblasts and Fully Differentiated Myotubes Reveal the Complexity of the Skeletal Muscle Differentiation Program

“…The MKK3, a dual-specificity MAP kinase, together with MKK4, MKK6, and MKK7, is an upstream activator of p38 MAP kinase involved in muscle differentiation (47). Expression of dominant-negative MKK3 severely inhibited the synthesis of MyoD, troponin T, p21 and p27, and myotube formation in C 2 C 12 cells (48). Thus, preferential accumulation of MKK3 in the C 2 C 12 myotubes corroborates previous studies indicating that MAP kinase cascade plays a critical role in skeletal muscle differentiation.…”

Serine/Threonine Kinase Mirk/Dyrk1B Is an Inhibitor of Epithelial Cell Migration and Is Negatively Regulated by the Met Adaptor Ran-binding Protein M

“…Mirk functions as a transcriptional coactivator that is activated by co-expressed MKK3 (7), a MAP kinase kinase that also can activate p38 MAP kinase (8 -10). Since p38MAPK also functions in muscle development (11) and p38 sequesters Mirk under certain cellular conditions (12), p38 may control Mirk function.…”