+publisher:"University of North Carolina" +contributor:("Mack, Christopher P.")

University of North Carolina

1. Medlin, Matthew Douglas. Sphingosine-1-phosphate and the RGS RhoGEFs regulate vascular smooth muscle phenotype.

Degree: Pathology and Laboratory Medicine, 2010, University of North Carolina

URL: https://cdr.lib.unc.edu/record/uuid:2d9e6b49-a8a7-4337-a948-9e4b380d322e

► The regulation of smooth muscle cell (SMC) differentiation is critical during vascular development, and perturbations in this process contribute to a number of cardiovascular pathologies… (more)

▼ The regulation of smooth muscle cell (SMC) differentiation is critical during vascular development, and perturbations in this process contribute to a number of cardiovascular pathologies including atherosclerosis, hypertension, and restenosis. We have shown that activation of RhoA by sphingosine-1 phosphate (S1P) stimulates SMC-specific gene expression by promoting the nuclear localization of the myocardin-related transcription factors (MRTFs). The aim of this dissertation is to dissect the precise mechanisms by which S1P regulates SMC phenotype. Using a combination of receptor-specific agonists and antagonists we identified S1P2 as the driving S1P receptor sub-type that regulates SMC-specific promoter activity and differentiation marker gene expression in primary SMC cultures. In addition, over expression of Gα12 or Gα13 increased SMC specific transcription, a result in excellent agreement with the known G-protein coupling properties of S1P2. Given previous studies on the interaction of Gα12/13 with the RGS subfamily of RhoGEFs (LARG, PRG, P115), we hypothesized that one or more of these RhoA activators was important in S1P-mediated SMC differentiation. While expression of each of the RGS RhoGEFs activated SMC specific transcription, LARG exhibited the most robust effect invoking a 10 to 15 fold increase SM22 and SM α-actin promoter activity. LARG expression also resulted in increased stress fiber formation and MRTF-A nuclear localization. Importantly, siRNA-mediated depletion of LARG (by approximately 90%) inhibited activation of RhoA by S1P and also inhibited the effects of S1P on endogenous SMC differentiation marker gene expression and SMC specific promoter activity. Finally, knockdown of LARG promoted SMC migration as measured by scratch wound and transwell assays. These findings indicate that stimulation of RhoA activity by S1P2-dependent activation of LARG plays a critical role in the regulation SMC phenotype. Interestingly P115 RhoGEF appears to regulate SMC migration in opposition to LARG. Despite the importance of RGS RhoGEF signaling little is known about their regulation. This thesis will explore the mechanisms regulating RGS RhoGEFs mediated RhoA activity and how differential RhoA activation may help modulate SMC phenotype. In conclusion these studies have improved our understanding the very complex means by which S1P mediated signaling regulates SMC phenotype and by extension normal and pathological vascular development. Advisors/Committee Members: Medlin, Matthew Douglas, Mack, Christopher P..

Subjects/Keywords: School of Medicine; Department of Pathology and Laboratory Medicine

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APA (6^th Edition):

Medlin, M. D. (2010). Sphingosine-1-phosphate and the RGS RhoGEFs regulate vascular smooth muscle phenotype. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:2d9e6b49-a8a7-4337-a948-9e4b380d322e

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Medlin, Matthew Douglas. “Sphingosine-1-phosphate and the RGS RhoGEFs regulate vascular smooth muscle phenotype.” 2010. Thesis, University of North Carolina. Accessed January 21, 2021. https://cdr.lib.unc.edu/record/uuid:2d9e6b49-a8a7-4337-a948-9e4b380d322e.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Medlin, Matthew Douglas. “Sphingosine-1-phosphate and the RGS RhoGEFs regulate vascular smooth muscle phenotype.” 2010. Web. 21 Jan 2021.

Vancouver:

Medlin MD. Sphingosine-1-phosphate and the RGS RhoGEFs regulate vascular smooth muscle phenotype. [Internet] [Thesis]. University of North Carolina; 2010. [cited 2021 Jan 21]. Available from: https://cdr.lib.unc.edu/record/uuid:2d9e6b49-a8a7-4337-a948-9e4b380d322e.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Medlin MD. Sphingosine-1-phosphate and the RGS RhoGEFs regulate vascular smooth muscle phenotype. [Thesis]. University of North Carolina; 2010. Available from: https://cdr.lib.unc.edu/record/uuid:2d9e6b49-a8a7-4337-a948-9e4b380d322e

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of North Carolina

2. Weise Cross, Laura. Regulation of Smooth Muscle Cell Phenotype by the RhoA Effectors mDia1 and mDia2.

Degree: Pathology and Laboratory Medicine, 2015, University of North Carolina

URL: https://cdr.lib.unc.edu/record/uuid:b656650d-84e2-48f7-ac8b-4135ba45a063

► Smooth muscle cells (SMCs) play an important role in vascular development and disease. Vascular SMCs undergo profound changes in phenotype in response to environmental cues… (more)

▼ Smooth muscle cells (SMCs) play an important role in vascular development and disease. Vascular SMCs undergo profound changes in phenotype in response to environmental cues that aid in development and vascular repair, but perturbations in the process contribute to many cardiovascular diseases, including atherosclerosis, restenosis, and hypertension. Therefore, it is critical to determine the mechanisms that control their phenotype. We have previously shown that the small GTPase RhoA promotes SMC differentiation through an SRF-dependent mechanism, and the RhoA effectors mDia1 and mDia2 mediate this effect through actin polymerization-dependent localization of the myocardin-related transcription factors (MRTFs). The primary aim of this dissertation is to further dissect the contributions of mDia signaling to SMC phenotype in vivo and in the nuclear compartment of the cell. Using a Cre-based approach, we overexpressed a dominant-negative mDia variant specifically in SMCs in a mouse model. We determined that inhibition of mDia signaling impaired cardiac structure and normal vessel morphology in a subset of developing mice. Adult mice exhibited altered SMC marker gene expression and abnormal SMC migration, indicating that mDia signaling has roles in both SMC differentiation and migration. In vitro studies revealed that mDia variants that preferentially localized to the nucleus significantly enhanced SMC-specific transcription, while those that were less nuclear exhibited reduced SMC transcriptional activity. These observations were also recapitulated with other RhoA signaling genes, implicating a model whereby nuclear RhoA signaling promotes SMC differentiation. Finally, little is known about the mechanisms regulating the expression of the RhoA signaling gene program. Using DNase I hypersensitivity methods coupled to high-throughput sequecing, deletion and mutation analysis, and a transgenic LacZ approach, we present novel evidence that this signaling pathway, including mDia2, may be regulated in an SRF-dependent manner. Because RhoA signaling promotes SRF-dependent transcription, we hypothesize that this mechanism serves as an auto-regulatory feed-forward circuit to promote SMC differentiation. Advisors/Committee Members: Weise Cross, Laura, Mack, Christopher P., Burridge, Keith, Furey, Terrence, Homeister, Jonathon, Wolberg, Alisa.

Subjects/Keywords: Pathology; Cytology; Molecular biology; School of Medicine; Department of Pathology and Laboratory Medicine

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Weise Cross, L. (2015). Regulation of Smooth Muscle Cell Phenotype by the RhoA Effectors mDia1 and mDia2. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:b656650d-84e2-48f7-ac8b-4135ba45a063

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Weise Cross, Laura. “Regulation of Smooth Muscle Cell Phenotype by the RhoA Effectors mDia1 and mDia2.” 2015. Thesis, University of North Carolina. Accessed January 21, 2021. https://cdr.lib.unc.edu/record/uuid:b656650d-84e2-48f7-ac8b-4135ba45a063.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Weise Cross, Laura. “Regulation of Smooth Muscle Cell Phenotype by the RhoA Effectors mDia1 and mDia2.” 2015. Web. 21 Jan 2021.

Vancouver:

Weise Cross L. Regulation of Smooth Muscle Cell Phenotype by the RhoA Effectors mDia1 and mDia2. [Internet] [Thesis]. University of North Carolina; 2015. [cited 2021 Jan 21]. Available from: https://cdr.lib.unc.edu/record/uuid:b656650d-84e2-48f7-ac8b-4135ba45a063.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Weise Cross L. Regulation of Smooth Muscle Cell Phenotype by the RhoA Effectors mDia1 and mDia2. [Thesis]. University of North Carolina; 2015. Available from: https://cdr.lib.unc.edu/record/uuid:b656650d-84e2-48f7-ac8b-4135ba45a063

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of North Carolina

3. Haynes, Elizabeth. GMFβ Controls Branched Actin Content and Lamellipodial Retraction in Fibroblasts.

Degree: Cell Biology and Physiology, 2015, University of North Carolina

URL: https://cdr.lib.unc.edu/record/uuid:e5600e13-7990-465c-b3d2-981e18a7c4e0

► The lamellipodium is an important structure for cell migration containing branched actin nucleated via the Arp2/3 complex. The formation of branched actin is relatively well… (more)

Subjects/Keywords: Cytology; School of Medicine; Department of Cell Biology and Physiology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Haynes, E. (2015). GMFβ Controls Branched Actin Content and Lamellipodial Retraction in Fibroblasts. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:e5600e13-7990-465c-b3d2-981e18a7c4e0

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Haynes, Elizabeth. “GMFβ Controls Branched Actin Content and Lamellipodial Retraction in Fibroblasts.” 2015. Thesis, University of North Carolina. Accessed January 21, 2021. https://cdr.lib.unc.edu/record/uuid:e5600e13-7990-465c-b3d2-981e18a7c4e0.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Haynes, Elizabeth. “GMFβ Controls Branched Actin Content and Lamellipodial Retraction in Fibroblasts.” 2015. Web. 21 Jan 2021.

Vancouver:

Haynes E. GMFβ Controls Branched Actin Content and Lamellipodial Retraction in Fibroblasts. [Internet] [Thesis]. University of North Carolina; 2015. [cited 2021 Jan 21]. Available from: https://cdr.lib.unc.edu/record/uuid:e5600e13-7990-465c-b3d2-981e18a7c4e0.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Haynes E. GMFβ Controls Branched Actin Content and Lamellipodial Retraction in Fibroblasts. [Thesis]. University of North Carolina; 2015. Available from: https://cdr.lib.unc.edu/record/uuid:e5600e13-7990-465c-b3d2-981e18a7c4e0

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of North Carolina

4. Mangum, Kevin. Genetic and Epigenetic Mechanisms Regulating Smooth Muscle Cell Differentiation.

Degree: Pathology and Laboratory Medicine, 2017, University of North Carolina

URL: https://cdr.lib.unc.edu/record/uuid:3e390865-999e-44be-b0f8-91bcda14f410

► Smooth muscle differentiation is a complex process, involving numerous molecular, genetic, and epigenetic mechanisms. Notably, smooth muscle cells (SMCs) retain marked plasticity in their ability… (more)

▼ Smooth muscle differentiation is a complex process, involving numerous molecular, genetic, and epigenetic mechanisms. Notably, smooth muscle cells (SMCs) retain marked plasticity in their ability to convert between synthetic and more differentiated contractile gene programs. In vascular diseases, including hypertension, atherosclerosis, and restenosis, SMCs dedifferentiate from their healthy, mature state to a more immature “phenotypically modulated” cell type capable of migrating, proliferating, and producing extracellular matrix, all of which contribute to disease. Additionally, genetic alterations in various components of the smooth muscle transcriptional machinery result in cardiovascular disease and even death. Thus, a more complete understanding of the exact mechanisms regulating SMC differentiation is crucial for the development of novel targets in the diagnosis and treatment of vascular disease. The work herein interrogates several points along the RhoA axis and defines their roles in SMC differentiation. First, the genetic and epigenetic mechanisms regulating expression of a smooth muscle-specific gene, GRAF3, are uncovered. GRAF3, also referred to as ARHGAP42, was first described by my collaborators in Joan Taylor’s Lab as a smooth muscle selective Rho-GAP essential for blood pressure control in mice. Single nucleotide polymorphisms in the GRAF3 gene were associated with changes in blood pressure, and the rs604723 T-allele variant located in a highly conserved DHS increased GRAF3 expression by promoting SRF binding to this region. In addition to SRF, we show that the transcription activity of this region as well as GRAF3 expression are controlled by the transcription factors, RBPJ and TEAD1. In subsequent chapters, we describe novel mechanisms regulating function of MRTF-A. Given that MRTF-A is essential for full activation of smooth muscle-specific gene expression, we hypothesize that these newly identified mechanisms regulate SMC differentiation. We describe our approach for identifying post-translational modifications and binding partners that regulate MRTF-A function. In our search for novel MRTF-A binding partners, we identified the putative histone lysine methyltransferase, PRDM6, and demonstrated that it was required for SMC differentiation. In overexpression experiments in COS-7 cells, we detected significant methylation on MRTF-A. Surprisingly, SMYD2 and SET7/9 strongly methylated MRTF-A, but PRDM6 did not. We found that SMDY2 methylated K27 within MRTF-A’s highly conserved basic nuclear localization signal. SMYD2-mediated methylation at K27 inhibited MRTF localization as well as MRTF-dependent activation of SMC transcription. Advisors/Committee Members: Mangum, Kevin, Mack, Christopher P., Bautch, Victoria, Liu, Jiandong, Sethupathy, Praveen, Taylor, Joan.

Subjects/Keywords: School of Medicine; Department of Pathology and Laboratory Medicine

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Mangum, K. (2017). Genetic and Epigenetic Mechanisms Regulating Smooth Muscle Cell Differentiation. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:3e390865-999e-44be-b0f8-91bcda14f410

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Mangum, Kevin. “Genetic and Epigenetic Mechanisms Regulating Smooth Muscle Cell Differentiation.” 2017. Thesis, University of North Carolina. Accessed January 21, 2021. https://cdr.lib.unc.edu/record/uuid:3e390865-999e-44be-b0f8-91bcda14f410.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Mangum, Kevin. “Genetic and Epigenetic Mechanisms Regulating Smooth Muscle Cell Differentiation.” 2017. Web. 21 Jan 2021.

Vancouver:

Mangum K. Genetic and Epigenetic Mechanisms Regulating Smooth Muscle Cell Differentiation. [Internet] [Thesis]. University of North Carolina; 2017. [cited 2021 Jan 21]. Available from: https://cdr.lib.unc.edu/record/uuid:3e390865-999e-44be-b0f8-91bcda14f410.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Mangum K. Genetic and Epigenetic Mechanisms Regulating Smooth Muscle Cell Differentiation. [Thesis]. University of North Carolina; 2017. Available from: https://cdr.lib.unc.edu/record/uuid:3e390865-999e-44be-b0f8-91bcda14f410

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of North Carolina

5. Blaker, Alicia L. Regulation of smooth muscle-specific transcription by serum response factor and formin homology domain containing protein 1.

Degree: Cell Biology and Physiology, 2008, University of North Carolina

URL: https://cdr.lib.unc.edu/record/uuid:72bddb54-ea9d-40d8-b281-cc9242e27f7b

► The regulation of vascular smooth muscle cell (SMC) differentiation is important during vasculogenesis, angiogenesis, and cardiovascular diseases, such as atherosclerosis and restenosis. Previous studies have… (more)

▼ The regulation of vascular smooth muscle cell (SMC) differentiation is important during vasculogenesis, angiogenesis, and cardiovascular diseases, such as atherosclerosis and restenosis. Previous studies have shown that SMC differentiation marker gene expression is regulated by serum response factor (SRF) and the myocardin family of SRF co-factors (myocardin and the myocardin-related factors, MRTF-A and MRTF-B). A major goal of the current studies was to identify post-translational modifications of SRF that regulate SMC-specific gene expression. By screening phosphorylation deficient and mimetic mutations in SRF -/- ES cells, I identified T159 as a phosphorylation site that significantly inhibits SMC-specific gene expression. In vitro and in vivo labeling studies demonstrated that T159 was phosphorylated by protein kinase PKA, and results from gel shift and chromatin immunoprecipitation assays demonstrated that T159 phosphorylation inhibited SRF binding to the CArG elements present within the promoters of the SMC-specific genes. Based upon the identification of Ubc9 in a yeast-two-hybrid screen for SRF binding proteins, I also tested the role of sumoylation on SRF activity. In vitro sumoylation assays identified K147 as the major SRF sumoylation site, but a sumoylation deficient K147R mutation had no effect on SRF-dependent SMC-specific gene expression. Our lab has also demonstrated that MRTF nuclear localization and activity is regulated by changes in actin dynamics, and a second goal was to determine whether the diaphanous formin, FHOD1, played a significant role in this process. Using RNAi techniques I demonstrated that FHOD1 was important for SMC differentiation marker gene expression in 10T1/2 and that over expression of a constitutively active version of FHOD1 strongly up-regulated SMC-specific promoter activity. Additional studies showed that phosphorylation of FHOD1 in the diaphanous auto-regulatory domain may contribute to FHOD1 activation and that FHOD1-mediated actin polymerization in the nucleus may be important for FHOD1's effects on MRTF activation. Taken together, my results indicate that PKA-mediated phosphorylation of SRF and FHOD1-mediated actin polymerization regulate SMC-transcription providing two novel signaling mechanisms for the control of SMC phenotype. Future experiments extending these findings should lead to a better understanding of SMC's role in cardiovascular disease and to targets for treating these conditions. Advisors/Committee Members: Blaker, Alicia L., Mack, Christopher P., University of North Carolina at Chapel Hill.

Subjects/Keywords: School of Medicine; Department of Cell Biology and Physiology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Blaker, A. L. (2008). Regulation of smooth muscle-specific transcription by serum response factor and formin homology domain containing protein 1. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:72bddb54-ea9d-40d8-b281-cc9242e27f7b

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Blaker, Alicia L. “Regulation of smooth muscle-specific transcription by serum response factor and formin homology domain containing protein 1.” 2008. Thesis, University of North Carolina. Accessed January 21, 2021. https://cdr.lib.unc.edu/record/uuid:72bddb54-ea9d-40d8-b281-cc9242e27f7b.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Blaker, Alicia L. “Regulation of smooth muscle-specific transcription by serum response factor and formin homology domain containing protein 1.” 2008. Web. 21 Jan 2021.

Vancouver:

Blaker AL. Regulation of smooth muscle-specific transcription by serum response factor and formin homology domain containing protein 1. [Internet] [Thesis]. University of North Carolina; 2008. [cited 2021 Jan 21]. Available from: https://cdr.lib.unc.edu/record/uuid:72bddb54-ea9d-40d8-b281-cc9242e27f7b.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Blaker AL. Regulation of smooth muscle-specific transcription by serum response factor and formin homology domain containing protein 1. [Thesis]. University of North Carolina; 2008. Available from: https://cdr.lib.unc.edu/record/uuid:72bddb54-ea9d-40d8-b281-cc9242e27f7b

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of North Carolina

6. Hinson, Jeremiah Stephen. The regulation of myocardin factor dependent transcription in vascular smooth muscle.

Degree: Pathology and Laboratory Medicine, 2008, University of North Carolina

URL: https://cdr.lib.unc.edu/record/uuid:75b1f541-b472-40c5-b545-5e09d8851000

► This work explores the role of the myocardin family of serum response factor (SRF) co-factors in smooth muscle cell (SMC) differentiation, and identifies novel modes… (more)

▼ This work explores the role of the myocardin family of serum response factor (SRF) co-factors in smooth muscle cell (SMC) differentiation, and identifies novel modes of regulating their activities. Extensive evidence indicates that SRF regulates muscle-specific gene expression by binding to conserved promoter regions known as CArG boxes. Myocardin and the myocardin-related transcription factors MRTF-A and MRTF-B are all capable of potently transactivating SRF-dependent gene expression. The sub-cellular localization of MRTFs is regulated by RhoA signaling, an established determinant of SMC marker gene activity. Studies included here demonstrate that the MRTFs are expressed in primary and cultured SMC and in multiple organs with a large SMC component, and that they are capable of upregulating SMC-specific gene activity in multipotential 10T1/2 cells. We demonstrate that the myocardin factors have dramatically different localization patterns and that the stimulation of SMC-specific transcription by certain RhoA-dependent agonists is likely mediated by increased nuclear translocation of the MRTFs. Gel shift assays were used to show that myocardin factor activity correlates well with SRF/CArG ternary complex formation, and that MRTF-SRF interactions are partially dependent upon CArG sequence. In a yeast-two-hybrid screen for novel SRF binding partners in aortic SMC, we identified four and a half LIM domain protein 2 (FHL2). We showed that FHL2 also interacted with all three myocardin factors and enhanced myocardin and MRTF-A-dependent transactivation of the SM α-actin, SM22, and cardiac ANF promoters by increasing the half-lives of these proteins. Treatment of cells with the proteasome inhibitors MG132 and lactacystin strongly upregulated myocardin factor protein levels and resulted in a substantial increase in ubiquitin immunoreactivity in MRTF-A immunoprecipitants. Importantly, these data are the first to indicate that the myocardin factors are regulated by proteasome-mediated degradation, and that SRF-dependent gene activity can be upregulated via inhibition of their degradation. We have further shown that the muscle-specific ring finger protein MuRF3 physically interacts with the myocardin factors and inhibits transactivation of the SM α-actin and SM22 promoters. MuRF3 also inhibited myocardin factor protein expression, and may act as an E3 ubiquitin ligase for this very important family of SRF co-factors. Advisors/Committee Members: Hinson, Jeremiah Stephen, Mack, Christopher P., University of North Carolina at Chapel Hill.

Subjects/Keywords: School of Medicine; Department of Pathology and Laboratory Medicine

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hinson, J. S. (2008). The regulation of myocardin factor dependent transcription in vascular smooth muscle. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:75b1f541-b472-40c5-b545-5e09d8851000

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Hinson, Jeremiah Stephen. “The regulation of myocardin factor dependent transcription in vascular smooth muscle.” 2008. Thesis, University of North Carolina. Accessed January 21, 2021. https://cdr.lib.unc.edu/record/uuid:75b1f541-b472-40c5-b545-5e09d8851000.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Hinson, Jeremiah Stephen. “The regulation of myocardin factor dependent transcription in vascular smooth muscle.” 2008. Web. 21 Jan 2021.

Vancouver:

Hinson JS. The regulation of myocardin factor dependent transcription in vascular smooth muscle. [Internet] [Thesis]. University of North Carolina; 2008. [cited 2021 Jan 21]. Available from: https://cdr.lib.unc.edu/record/uuid:75b1f541-b472-40c5-b545-5e09d8851000.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Hinson JS. The regulation of myocardin factor dependent transcription in vascular smooth muscle. [Thesis]. University of North Carolina; 2008. Available from: https://cdr.lib.unc.edu/record/uuid:75b1f541-b472-40c5-b545-5e09d8851000

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of North Carolina

7. Staus, Dean P. The Diaphanous-Related Formins: Dynamic Regulators of Smooth Muscle Cell-Specific Gene Transcription.

Degree: Pathology and Laboratory Medicine, 2009, University of North Carolina

URL: https://cdr.lib.unc.edu/record/uuid:c9d174d9-7adb-4ae7-8d0c-b247017e5ce9

► We and others have previously shown that RhoA-dependent actin polymerization stimulates SMC-specific gene transcription by promoting the nuclear accumulation of the myocardin-related transcription factors (MRTF)-A… (more)

▼ We and others have previously shown that RhoA-dependent actin polymerization stimulates SMC-specific gene transcription by promoting the nuclear accumulation of the myocardin-related transcription factors (MRTF)-A and -B. Very little is known about the downstream RhoA effectors that mediate this response, and the goal of the studies described herein was to define the role of the diaphanous-related formins (DRFs) in regulating smooth muscle cell (SMC) differentiation. The DRFs mDia1 and mDia2 are highly expressed in cultured SMCs and in tissues containing a high smooth muscle component. Activation of mDia1 or mDia2 by RhoA stimulated actin polymerization, MRTF nuclear accumulation, and SMC-specific gene transcription. Interestingly, we found that phosphorylation of the Diaphanous Autoregulatory Domain (DAD) by Rho-kinase also stimulated mDia2 activity and SM-marker gene expression. Knockdown of mDia1/2 using siRNA significantly attenuated expression of numerous SM-marker genes in primary aortic SMCs. While we originally attributed these findings to the regulation of cytoplasmic actin dynamics by the DRFs, recent evidence linking nuclear globular (G)-actin to MRTF nuclear export led us to investigate a possible role for the DRFs in the nucleus. We found that mDia2, but not mDia1 or FHOD1, accumulated in the nucleus following treatment with leptomycin, an inhibitor of Crm-1 dependent nuclear export. Deletion and mutation analyses identified nuclear localization sequences (NLS) in the core formin homology 2 (FH2) domain and extreme N-terminus, and a leucine-rich nuclear export sequence (NES) was identified in the C-terminus of mDia2. Importantly, mDia2 variants that were excluded from the nucleus did not stimulate SMC-specific gene transcription and MRTF-B nuclear accumulation as well as wild-type mDia2. Taken together, these data support a model in which mDia2 activity in the nucleus and cytoplasm depletes cellular G-actin pools resulting in MRTF nuclear accumulation and activation of SMC-specific gene transcription. Advisors/Committee Members: Staus, Dean P., Mack, Christopher P., University of North Carolina at Chapel Hill.

Subjects/Keywords: School of Medicine; Department of Pathology and Laboratory Medicine

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Staus, D. P. (2009). The Diaphanous-Related Formins: Dynamic Regulators of Smooth Muscle Cell-Specific Gene Transcription. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:c9d174d9-7adb-4ae7-8d0c-b247017e5ce9

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Staus, Dean P. “The Diaphanous-Related Formins: Dynamic Regulators of Smooth Muscle Cell-Specific Gene Transcription.” 2009. Thesis, University of North Carolina. Accessed January 21, 2021. https://cdr.lib.unc.edu/record/uuid:c9d174d9-7adb-4ae7-8d0c-b247017e5ce9.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Staus, Dean P. “The Diaphanous-Related Formins: Dynamic Regulators of Smooth Muscle Cell-Specific Gene Transcription.” 2009. Web. 21 Jan 2021.

Vancouver:

Staus DP. The Diaphanous-Related Formins: Dynamic Regulators of Smooth Muscle Cell-Specific Gene Transcription. [Internet] [Thesis]. University of North Carolina; 2009. [cited 2021 Jan 21]. Available from: https://cdr.lib.unc.edu/record/uuid:c9d174d9-7adb-4ae7-8d0c-b247017e5ce9.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Staus DP. The Diaphanous-Related Formins: Dynamic Regulators of Smooth Muscle Cell-Specific Gene Transcription. [Thesis]. University of North Carolina; 2009. Available from: https://cdr.lib.unc.edu/record/uuid:c9d174d9-7adb-4ae7-8d0c-b247017e5ce9

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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Open Access Theses and Dissertations