scholarly journals The Cytoskeleton-associated PDZ-LIM Protein, ALP, Acts on Serum Response Factor Activity to Regulate Muscle Differentiation

2007 ◽  
Vol 18 (5) ◽  
pp. 1723-1733 ◽  
Author(s):  
Pascal Pomiès ◽  
Mohammad Pashmforoush ◽  
Cristina Vegezzi ◽  
Kenneth R. Chien ◽  
Charles Auffray ◽  
...  
Keyword(s):  
Serum Response Factor ◽  
Critical Role ◽  
Muscle Differentiation ◽  
Actin Dynamics ◽  
Response Factor ◽  
Cytoskeletal Regulation ◽  
Expression Construct ◽  
Filament Bundles ◽  
Serum Response

In this report, an antisense RNA strategy has allowed us to show that disruption of ALP expression affects the expression of the muscle transcription factors myogenin and MyoD, resulting in the inhibition of muscle differentiation. Introduction of a MyoD expression construct into ALP-antisense cells is sufficient to restore the capacity of the cells to differentiate, illustrating that ALP function occurs upstream of MyoD. It is known that MyoD is under the control of serum response factor (SRF), a transcriptional regulator whose activity is modulated by actin dynamics. A dramatic reduction of actin filament bundles is observed in ALP-antisense cells and treatment of these cells with the actin-stabilizing drug jasplakinolide stimulates SRF activity and restores the capacity of the cells to differentiate. Furthermore, we show that modulation of ALP expression influences SRF activity, the level of its coactivator, MAL, and muscle differentiation. Collectively, these results suggest a critical role of ALP on muscle differentiation, likely via cytoskeletal regulation of SRF.

scholarly journals Critical Role of Serum Response Factor in Pulmonary Myofibroblast Differentiation Induced by TGF-β

2009 ◽  
Vol 41 (3) ◽  
pp. 332-338 ◽  
Author(s):  
Nathan Sandbo ◽  
Steven Kregel ◽  
Sebastien Taurin ◽  
Sangeeta Bhorade ◽  
Nickolai O. Dulin
Keyword(s):  
Serum Response Factor ◽  
Critical Role ◽  
Myofibroblast Differentiation ◽  
Response Factor ◽  
Serum Response

scholarly journals Serum response factor is an essential transcription factor in megakaryocytic maturation

Blood ◽  
2010 ◽  
Vol 116 (11) ◽  
pp. 1942-1950 ◽  
Author(s):  
Stephanie Halene ◽  
Yuan Gao ◽  
Katherine Hahn ◽  
Stephanie Massaro ◽  
Joseph E. Italiano ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Serum Response Factor ◽  
Critical Role ◽  
Response Factor ◽  
Megakaryoblastic Leukemia ◽  
Serum Response ◽  
Essential Transcription Factor

Abstract Serum response factor (Srf) is a MADS–box transcription factor that is critical for muscle differentiation. Its function in hematopoiesis has not yet been revealed. Mkl1, a cofactor of Srf, is part of the t(1;22) translocation in acute megakaryoblastic leukemia, and plays a critical role in megakaryopoiesis. To test the role of Srf in megakaryocyte development, we crossed Pf4-Cre mice, which express Cre recombinase in cells committed to the megakaryocytic lineage, to SrfF/F mice in which functional Srf is no longer expressed after Cre-mediated excision. Pf4-Cre/SrfF/F knockout (KO) mice are born with normal Mendelian frequency, but have significant macrothrombocytopenia with approximately 50% reduction in platelet count. In contrast, the BM has increased number and percentage of CD41+ megakaryocytes (WT: 0.41% ± 0.06%; KO: 1.92% ± 0.12%) with significantly reduced ploidy. KO mice show significantly increased megakaryocyte progenitors in the BM by FACS analysis and CFU-Mk. Megakaryocytes lacking Srf have abnormal stress fiber and demarcation membrane formation, and platelets lacking Srf have abnormal actin distribution. In vitro and in vivo assays reveal platelet function defects in KO mice. Critical actin cytoskeletal genes are down-regulated in KO megakaryocytes. Thus, Srf is required for normal megakaryocyte maturation and platelet production partly because of regulation of cytoskeletal genes.

scholarly journals The Aging Vasculature: Glucose Tolerance, Hypoglycemia and the Role of the Serum Response Factor

2021 ◽  
Vol 8 (5) ◽  
pp. 58
Author(s):  
Hazel Aberdeen ◽  
Kaela Battles ◽  
Ariana Taylor ◽  
Jeranae Garner-Donald ◽  
Ana Davis-Wilson ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Molecular Mechanisms ◽  
Serum Response Factor ◽  
Response Factor ◽  
Homeostatic Control ◽  
Older Americans ◽  
The Subject ◽  
Serum Response

The fastest growing demographic in the U.S. at the present time is those aged 65 years and older. Accompanying advancing age are a myriad of physiological changes in which reserve capacity is diminished and homeostatic control attenuates. One facet of homeostatic control lost with advancing age is glucose tolerance. Nowhere is this more accentuated than in the high proportion of older Americans who are diabetic. Coupled with advancing age, diabetes predisposes affected subjects to the onset and progression of cardiovascular disease (CVD). In the treatment of type 2 diabetes, hypoglycemic episodes are a frequent clinical manifestation, which often result in more severe pathological outcomes compared to those observed in cases of insulin resistance, including premature appearance of biomarkers of senescence. Unfortunately, molecular mechanisms of hypoglycemia remain unclear and the subject of much debate. In this review, the molecular basis of the aging vasculature (endothelium) and how glycemic flux drives the appearance of cardiovascular lesions and injury are discussed. Further, we review the potential role of the serum response factor (SRF) in driving glycemic flux-related cellular signaling through its association with various proteins.

scholarly journals Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics

2012 ◽  
Vol 109 (38) ◽  
pp. E2523-E2532 ◽  
Author(s):  
Henning Beck ◽  
Kevin Flynn ◽  
Katrin S. Lindenberg ◽  
Heinz Schwarz ◽  
Frank Bradke ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Serum Response Factor ◽  
Mitochondrial Dynamics ◽  
Actin Dynamics ◽  
Response Factor ◽  
Signaling Axis ◽  
Mitochondrial Number ◽  
Mitochondrial Networks ◽  
The Impact ◽  
Serum Response

Aberrant mitochondrial function, morphology, and transport are main features of neurodegenerative diseases. To date, mitochondrial transport within neurons is thought to rely mainly on microtubules, whereas actin might mediate short-range movements and mitochondrial anchoring. Here, we analyzed the impact of actin on neuronal mitochondrial size and localization. F-actin enhanced mitochondrial size and mitochondrial number in neurites and growth cones. In contrast, raising G-actin resulted in mitochondrial fragmentation and decreased mitochondrial abundance. Cellular F-actin/G-actin levels also regulate serum response factor (SRF)-mediated gene regulation, suggesting a possible link between SRF and mitochondrial dynamics. Indeed, SRF-deficient neurons display neurodegenerative hallmarks of mitochondria, including disrupted morphology, fragmentation, and impaired mitochondrial motility, as well as ATP energy metabolism. Conversely, constitutively active SRF-VP16 induced formation of mitochondrial networks and rescued huntingtin (HTT)-impaired mitochondrial dynamics. Finally, SRF and actin dynamics are connected via the actin severing protein cofilin and its slingshot phosphatase to modulate neuronal mitochondrial dynamics. In summary, our data suggest that the SRF-cofilin-actin signaling axis modulates neuronal mitochondrial function.

2007 Russell Ross Memorial Lectureship in Vascular Biology—Epigenetic Control of Vascular Smooth Muscle Differentiation in Development and Disease

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Gary K. Owens
Keyword(s):  
Smooth Muscle ◽  
Vascular Injury ◽  
Serum Response Factor ◽  
Critical Role ◽  
Conditional Knockout ◽  
Phenotypic Switching ◽  
Marker Genes ◽  
List Type ◽  
Response Factor ◽  
Serum Response

There is clear evidence that alterations in the differentiated state of the smooth muscle cell (SMC) play a key role in the pathogenesis of a number of major human diseases, including atherosclerosis and postan-gioplasty restenosis. This process is referred to as “phenotypic switching” and likely evolved to promote repair of vascular injury. However, the mechanisms controlling phenotypic switching as well as normal differentiation of SMCs in vivo are poorly understood. This talk will provide an overview of molecular mechanisms that control differentiation of SMCs during vascular development. A particular focus will be to consider the role of CArG elements found within the promoters of many SMC differentiation marker genes, as well as regulation of their activity by serum response factor and the potent SMC-selective serum response factor coactivator myocardin. In addition, I will summarize recent work in our laboratory showing that SMC- and gene-locus–selective changes in chromatin structure play a critical role both in normal control of SMC differentiation and in phenotypic switching in response to vascular injury. Finally, I will present evidence based on conditional knockout experiments in mice showing that krupple-like factor 4 is induced in SMCs after vascular injury and regulates SMC phenotypic switching and growth through: binding to G/C repressor elements located in close proximity of CArG elements within the promoters of many SMC marker genes, suppressing expression of myocardin, and inducing epigenetic modifications of SMC marker gene loci associated with chromatin condensation and transcriptional silencing. Supported by NIH grants P01 HL19242, R37 HL57353, and R01 HL 38854.

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