ABSTRACT
Cellular transformation into myofibroblasts is a central physiological process enabling tissue repair. Its deregulation promotes fibrosis and carcinogenesis. TGF-ß is the main inducer of the contractile gene program that drives myofibroblast differentiation from various precursor cell types. Crucial regulators of this transcriptional program are serum response factor (SRF) and its cofactor MKL1 (also known as MRTF-A). However, the exact mechanism of the crosstalk between TGF-ß signaling and MKL1 remains unclear. Here, we report the discovery of a novel MKL1 variant/isoform, MKL1_S, transcribed from an alternative promoter and uncover a novel translation start for the published human isoform, MKL1_L. Using a human adipose-derived mesenchymal stem cell differentiation model, we show that TGF-ß specifically upregulates MKL1_S during the initial phase of myofibroblast differentiation. We identified a functional N-terminal motif in MKL1_S that allows specific induction of a group of genes including the extracellular matrix (ECM) modifiers MMP16 and SPOCK3/testican-3. We propose that TGF-ß-mediated induction of MKL1_S initiates progression to later stages of differentiation towards a stationary myofibroblast.
Subject(s)
Cell Differentiation , DNA-Binding Proteins/metabolism , Myofibroblasts/physiology , Oncogene Proteins, Fusion/metabolism , Transforming Growth Factor beta1/physiology , Active Transport, Cell Nucleus , Amino Acid Sequence , Base Sequence , Cell Nucleus/metabolism , Codon, Initiator , DNA-Binding Proteins/genetics , HEK293 Cells , HeLa Cells , Humans , Matrix Metalloproteinase 16/genetics , Matrix Metalloproteinase 16/metabolism , Molecular Sequence Data , Oncogene Proteins, Fusion/genetics , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Structure, Tertiary , Trans-Activators , Transcription, Genetic , Up-RegulationABSTRACT
Megakaryoblastic leukemia protein-1 (MKL1), also termed MAL, MRTF-A, and BSAC, belongs to the MRTF family of transcription factors that share evolutionary conserved domains required for actin-binding, homo- and heterodimerization, high-order chromatin organization and transcriptional activation. MKL1 regulates many processes, including muscle cell differentiation, cardiovascular development, remodeling of neuronal networks in the developing and adult brain, megakaryocytic differentiation and migration, modulation of cellular motile functions and epithelial-mesenchymal transition. Moreover, deregulation by genetic alterations and/or altered expression of MKL1 can contribute to a number of pathological processes such as coronary artery disease, sarcopenia, acute megakaryoblastic leukemia, and cancer. In this article, we review the structure, regulation and biological functions of MKL1. In addition, we discuss recent evidence that strongly suggests a dual role for MKL1 in oncogenic mechanisms, as a tumor-promoting or tumor-suppressing molecule. Future studies will be necessary to evaluate the potential clinical implications of MKL1 expression and activation in cancer.
