Megakaryoblastic leukemia-1/2, a transcriptional co-activator of serum response factor, is required for skeletal myogenic differentiation.
Serum response factor (SRF) is required for the expression of a wide variety of muscle-specific genes that are expressed upon differentiation and is thus required for both striated and smooth muscle differentiation in addition to its role in regulating growth factor-inducible genes. A heart and smooth muscle-specific SRF co-activator, myocardin, ... has been shown to be required for cardiac development and smooth muscle differentiation. However, no such co-factors of SRF have been identified in the skeletal myogenic differentiation program. Myocardin and the related transcription factor megakaryoblastic leukemia-1 (MKL1/MAL/MRTF-A) can strongly potentiate the activity of SRF. Here we report the cloning of the third member of the myocardin/MKL family in humans, MKL2. MKL2 binds to and activates SRF similar to myocardin and MKL1. To determine the role of these factors in skeletal myogenic differentiation we used a dominant negative MKL2 to show that the MKL family of proteins is required for skeletal myogenic differentiation. Expression of the dominant negative protein in C2C12 skeletal myoblasts blocked the differentiation-induced expression of the SRF target genes skeletal alpha-actin and alpha-myosin heavy chain and blocked differentiation of the myoblasts to myotubes in vitro. C2C12 cells express both MKL1 and MKL2, but not myocardin, implicating MKL1 and/or MKL2 in the requirement for skeletal myogenic differentiation. MKL1 was predominantly cytoplasmic in C2C12 cells, with a small amount in the nucleus, however, no movement of MKL1 to the nucleus was observed upon differentiation.
Mesh Terms:
Amino Acid Sequence, Animals, Cell Differentiation, Cell Line, Cloning, Molecular, DNA-Binding Proteins, Humans, Mice, Molecular Sequence Data, Muscle Fibers, Skeletal, Oncogene Proteins, Fusion, Protein Binding, Serum Response Factor, Tissue Distribution, Transcription Factors, Transcriptional Activation
Amino Acid Sequence, Animals, Cell Differentiation, Cell Line, Cloning, Molecular, DNA-Binding Proteins, Humans, Mice, Molecular Sequence Data, Muscle Fibers, Skeletal, Oncogene Proteins, Fusion, Protein Binding, Serum Response Factor, Tissue Distribution, Transcription Factors, Transcriptional Activation
J. Biol. Chem.
Date: Oct. 24, 2003
PubMed ID: 14565952
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