Potentiation of serum response factor activity by a family of myocardin-related transcription factors

Wang, Da Zhi; Li, Shijie; Hockemeyer, Dirk; Sutherland, Lillian B.; Wang, Zhigao; Schratt, Gerhard; Richardson, James A.; Nordheim, Alfred; Olson, Eric N.

doi:10.1073/pnas.222561499

Cited by 438 publications

(501 citation statements)

References 31 publications

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“…Here we report the cloning of a third member of the myocardin/MKL family, MKL2, in humans. A mouse homologue of this gene, MRTF-B, was also recently identified and a fragment of the gene was previously identified as MAL16 (33,36). We find that MKL2 is broadly expressed, with strong expression in skeletal muscle, and can interact with SRF and activate many CArG box-containing promoters.…”

mentioning

confidence: 53%

“…MKL2 Is a Strong Transactivator of CArG Box-dependent Promoters-Because MKL1 and myocardin strongly activate CArG box containing promoters (15,35,36), we checked whether overexpression of MKL2 could also activate CArG box-dependent reporter genes and act as a transcriptional coactivator of SRF. To test this we co-expressed MKL1, MKL2, or an N-terminal deletion of MKL2 (MKL2⌬N) that lacks 71 aa such that it starts at the beginning of the MKL homology domain similar to MKL1 (Fig.…”

Section: Identification and Expression Of Human Mkl2-wementioning

confidence: 99%

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Megakaryoblastic Leukemia-1/2, a Transcriptional Co-activator of Serum Response Factor, Is Required for Skeletal Myogenic Differentiation

Selvaraj

Prywes

2003

Journal of Biological Chemistry

127

146

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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 ␣-actin and ␣-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.

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mentioning

confidence: 53%

Section: Identification and Expression Of Human Mkl2-wementioning

confidence: 99%

Megakaryoblastic Leukemia-1/2, a Transcriptional Co-activator of Serum Response Factor, Is Required for Skeletal Myogenic Differentiation

Selvaraj

Prywes

2003

Journal of Biological Chemistry

127

146

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“…These findings further support results of the present studies indicating that myocardin alone is insufficient to initiate the entire SMC differentiation program. Of interest, Wang et al 29 showed that expression of the myocardin-related factors, MRTF-A/MAL/MKL1/BSAC and MRTF-B/MKL2, preceded the expression of myocardin, and they were expressed throughout the embryo at E10.5. In addition, they showed that MRTF-A/MAL/MKL1/BSAC potently activated SM22␣ transcription, even in the absence of myocardin.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, they showed that MRTF-A/MAL/MKL1/BSAC potently activated SM22␣ transcription, even in the absence of myocardin. 29 It is thus possible that these myocardin-related factors may also contribute to initial expression of early SMC markers.…”

Section: Discussionmentioning

confidence: 99%

Forced Expression of Myocardin Is Not Sufficient for Induction of Smooth Muscle Differentiation in Multipotential Embryonic Cells

Yoshida

Kawai-Kowase

Owens

2004

ATVB

103

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Objective-Myocardin, a coactivator of serum response factor, has been shown to be required for expression of multiple CArG-dependent smooth muscle cell (SMC) marker genes. The aim of the present study was to determine whether myocardin alone is sufficient to induce SMC lineage in multipotential stem cells as evidenced by activation of the entire SMC differentiation program. Methods and Results-Overexpression of myocardin induced only a subset of SMC marker genes, including smooth muscle (SM) ␣-actin, SM-myosin heavy chain (MHC), SM22␣, calponin, and desmin in A404 SMC precursor cells, whereas expression of smoothelin-B, aortic carboxypeptidase-like protein, and focal adhesion kinase-related nonkinase, whose promoters lack efficacious CArG elements, was not induced. Similar results were obtained in cultured SMCs, 10T1/2 cells, and embryonic stem cells. Moreover, myocardin inappropriately induced expression of skeletal and cardiac CArG-dependent genes in cultured SMCs. Stable overexpression of dominant-negative myocardin in A404 cells resulted in impaired induction of SM ␣-actin and SM-MHC by all trans-retinoic acid but had no effect on induction of smoothelin-B and aortic carboxypeptidase-like protein expression. Conclusions-Taken together with previous studies, results demonstrate that myocardin is required for the induction of CArG-dependent SMC marker genes but is not sufficient to initiate the complete SMC differentiation program. Key Words: smooth muscle cells Ⅲ transcriptional coactivator Ⅲ serum response factor Ⅲ CArG element S mooth muscle cells (SMCs) play pivotal roles in vascular development and in diseases such as atherosclerosis. Under normal circumstances, differentiated SMCs are highly specialized for their contractile function and express a unique repertoire of contractile proteins, contractile agonist receptors, and signaling molecules to perform this function. 1 The expression levels of most of these SMC-specific/SMCselective proteins reflect the differentiation state of SMCs. 1 Therefore, these proteins are considered as useful markers for studying the control of SMC differentiation. See page 1535There has been considerable progress in elucidation of molecular mechanisms that regulate cell-selective expression of SMC differentiation markers in recent years. For example, expression of most SMC differentiation markers characterized to date, including smooth muscle (SM) ␣-actin, 2 SMmyosin heavy chain (MHC), 3 SM22␣, 4 calponin, 5 and desmin, 6 has been shown to be regulated at the transcriptional level and dependent on multiple CArG elements located within their promoter-enhancer regions. The CArG element has the general sequence motif, CC(A/T-rich) 6 GG and binds the ubiquitously expressed transcription factor, serum response factor (SRF). 7 CArG elements are also required for expression of many growth factor-inducible genes including c-fos and egr-1, 7 and a major challenge has been to identify mechanisms by which CArG-SRF-dependent mechanisms can simultaneously contribute to the apparently dis...

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“…Myocardin-related transcription factors (MRTFs) have been shown to activate serum response factor (SRF) [9][10][11] upon dissociation from G-actin 12 , providing muscle growth and regeneration 13,14 . SRF is co-activated by myocardin 15 or MRTFs A and B 16 .…”

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confidence: 99%

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

et al. 2014

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Gradual occlusion of coronary arteries may result in reversible loss of cardiomyocyte function (hibernating myocardium), which is amenable to therapeutic neovascularization. The role of myocardin-related transcription factors (MRTFs) co-activating serum response factor (SRF) in this process is largely unknown. Here we show that forced MRTF-A expression induces CCN1 and CCN2 to promote capillary proliferation and pericyte recruitment, respectively. We demonstrate that, upon G-actin binding, thymosin 4 (T 4), induces MRTF translocation to the nucleus, SRF-activation and CCN1/2 transcription. In a murine ischaemic hindlimb model, MRTF-A or T 4 promotes neovascularization, whereas loss of MRTF-A/B or CCN1-function abrogates the T 4 effect. We further show that, in ischaemic rabbit hindlimbs, MRTF-A as well as T 4 induce functional neovascularization, and that this process is inhibited by angiopoietin-2, which antagonizes pericyte recruitment. Moreover, MRTF-A improves contractile function of chronic hibernating myocardium of pigs to a level comparable to that of transgenic pigs overexpressing T 4 (T 4tg). We conclude that MRTF-A promotes microvessel growth (via CCN1) and maturation (via CCN2), thereby enabling functional improvement of ischaemic muscle tissue.

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Potentiation of serum response factor activity by a family of myocardin-related transcription factors

Cited by 438 publications

References 31 publications

Megakaryoblastic Leukemia-1/2, a Transcriptional Co-activator of Serum Response Factor, Is Required for Skeletal Myogenic Differentiation

Megakaryoblastic Leukemia-1/2, a Transcriptional Co-activator of Serum Response Factor, Is Required for Skeletal Myogenic Differentiation

Forced Expression of Myocardin Is Not Sufficient for Induction of Smooth Muscle Differentiation in Multipotential Embryonic Cells

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

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