Dual Role of CREB in The Regulation of VSMC Proliferation: Mode of Activation Determines Pro- or Anti-Mitogenic Function

Hudson, Claire; Kimura, Tomomi; Sala-Newby, Graciela B.; Newby, Andrew C.; Bond, Mark

doi:10.1038/s41598-018-23199-4

Cited by 24 publications

(17 citation statements)

References 52 publications

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“…The activation of AKT/mTOR and MAPK/Erk signaling cascades by apelin phosphorylates p70S6K leads to HUVEC proliferation . Serine 133 phosphorylation of the cAMP responsive element binding protein (CREB) is at the endpoint of various signaling pathways, like growth factor signaling, and regulates vascular smooth muscle cell proliferation . That EV/Exs activated AKT and Erk cascade in HUVEC and phosphorylated the same residues of p70S6K and CREB, strongly suggest the implication of these cascades in EV/Exs‐induced proliferation of endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

Hocine

Brunel

Chen

et al. 2019

Stem Cells Translational Medicine

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The positive effects of therapeutic human allogeneic cardiac stem/progenitor cells (hCPC) in terms of cardiac repair/regeneration are very likely mediated by paracrine effects. Our previous studies revealed the advantageous immune interactions of allogeneic hCPC and proposed them as part of the positive paracrine effects occurring upon their application postmyocardial infarction (MI). Currently, extracellular vesicles/exosomes (EV/Exs) released by stem/progenitor cells are also proposed as major mediators of paracrine effects of therapeutic cells. Along this line, we evaluated contribution of EV/Exs released by therapeutic hCPC to the benefit of their successful allogeneic clinical application. Through tailored allogeneic in vitro human assay models mimicking the clinical setting, we demonstrate that hCPC‐released EV/Exs were rapidly and efficiently up‐taken by chief cellular actors of cardiac repair/regeneration. This promoted MAPK/Erk1/2 activation, migration, and proliferation of human leukocyte antigens (HLA)‐mismatched hCPC, mimicking endogenous progenitor cells and cardiomyocytes, and enhanced endothelial cell migration, growth, and organization into tube‐like structures through activation of several signaling pathways. EV/Exs also acted as pro‐survival stimuli for HLA‐mismatched monocytes tuning their phenotype toward an intermediate anti‐inflammatory pro‐angiogenic phenotype. Thus, while positively impacting the intrinsic regenerative and angiogenic programs, EV/Exs released by therapeutic allogeneic hCPC can also actively contribute to shaping MI‐inflammatory environment, which could strengthen the benefits of hCPC allogeneic interactions. Collectively, our data might forecast the application of allogeneic hCPC followed by their cell‐free EV/Exs as a strategy that will not only elicit the cell‐contact mediated reparative/regenerative immune response but also have the desired long‐lasting effects through the EV/Exs. stem cells translational medicine 2019;8:911&924

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Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

Hocine

Brunel

Chen

et al. 2019

Stem Cells Translational Medicine

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“…The transcriptional coactivators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) also play an important role in linking actin cytoskeleton dynamics to gene expression and changes in cell behaviour [203]. In the nucleus, YAP and TAZ interact with members of the TEA domain (TEAD) transcription factors and several other components of the transcriptional machinery, to regulate gene expression [204,205] and promote cell proliferation [206]. The functions of YAP and TAZ are negatively regulated by the Hippo pathway kinases MST and LATS [207,208].…”

Section: The Role Of Actin Cytoskeleton Remodellingmentioning

confidence: 99%

“…Several studies suggested that CREB contributes towards the anti-mitogenic effects of cAMP in VSMC (see Figure 3). For example, stimuli that elevate cAMP and inhibit VSMC proliferation are associated with increased CREB activity [47,91,205,227]. Inhibition of CREB using siRNA-mediated silencing or expression of dominant-negative CREB increases VSMC proliferation [228,229,230], whereas expression of constitutively active CREB mutants is inhibitory [47,228,230].…”

Section: The Role Of Crebmentioning

confidence: 99%

Ending Restenosis: Inhibition of Vascular Smooth Muscle Cell Proliferation by cAMP

Smith

Newby

Bond

2019

Cells

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Increased vascular smooth muscle cell (VSMC) proliferation contributes towards restenosis after angioplasty, vein graft intimal thickening and atherogenesis. The second messenger 3′ 5′ cyclic adenosine monophosphate (cAMP) plays an important role in maintaining VSMC quiescence in healthy vessels and repressing VSMC proliferation during resolution of vascular injury. Although the anti-mitogenic properties of cAMP in VSMC have been recognised for many years, it is only recently that we gained a detailed understanding of the underlying signalling mechanisms. Stimuli that elevate cAMP in VSMC inhibit G1-S phase cell cycle progression by inhibiting expression of cyclins and preventing S-Phase Kinase Associated Protein-2 (Skp2-mediated degradation of cyclin-dependent kinase inhibitors. Early studies implicated inhibition of MAPK signalling, although this does not fully explain the anti-mitogenic effects of cAMP. The cAMP effectors, Protein Kinase A (PKA) and Exchange Protein Activated by cAMP (EPAC) act together to inhibit VSMC proliferation by inducing Cyclic-AMP Response Element Binding protein (CREB) activity and inhibiting members of the RhoGTPases, which results in remodelling of the actin cytoskeleton. Cyclic-AMP induced actin remodelling controls proliferation by modulating the activity of Serum Response Factor (SRF) and TEA Domain Transcription Factors (TEAD), which regulate expression of genes required for proliferation. Here we review recent research characterising these mechanisms, highlighting novel drug targets that may allow the anti-mitogenic properties of cAMP to be harnessed therapeutically to limit restenosis.

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“…Previous studies have shown CRTC2-deficient mice have normal glucose levels during both feeding and fasting conditions without any effects on hepatic glucose production [33], suggesting the contribution of CRTC2 to glucose homeostasis is limited. Additionally, serum increases the proliferation of vascular smooth muscle cells by inducing phosphorylation of CREB without regulating CRTC2 [34]. Thus, our results suggest DSCR1-4 induces gluconeogenesis by increasing the phosphorylation of CREB independently of CRTC2 phosphorylation.…”

Section: Discussionmentioning

confidence: 52%

A single extra copy of Down syndrome critical region 1–4 results in impaired hepatic glucose homeostasis

Seo

Chau

Baek

et al. 2019

Molecular Metabolism

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Objectives During fasting, hepatic gluconeogenesis is induced to maintain energy homeostasis. Moreover, abnormal dysregulation of hepatic glucose production is commonly observed in type 2 diabetes. However, the signaling components controlling hepatic glucose production to maintain normal glucose levels are not fully understood. Here, we examined the physiological role of Down syndrome critical region 1–4 (DSCR1-4), an endogenous calcineurin signaling inhibitor in the liver that mediates metabolic adaptation to fasting. Methods We assessed the effect of cyclosporine A, an inhibitor of calcineurin signaling on gluconeogenic gene expression in primary hepatocytes. DSCR1-4 expression was examined in diet- and genetically-induced mouse models of obesity. We also investigated the metabolic phenotype of a single extra copy of DSCR1-4 in transgenic mice and how DSCR1-4 regulates glucose homeostasis in the liver. Results Treatment with cyclosporin A increased hepatic glucose production and gluconeogenic gene expression. The expression of DSCR1-4 was induced by refeeding and overexpressed in obese mouse livers. Moreover, transgenic mice with a single extra copy of DSCR1-4 exhibited pyruvate intolerance and impaired glucose homeostasis. Mechanistically, DSCR1-4 overexpression increased phosphorylation of the cAMP response element-binding protein, which led to elevated expression levels of gluconeogenic genes and, thus, enhanced hepatic glucose production during fasting. Conclusion A single extra copy of DSCR1-4 results in dysregulated hepatic glucose homeostasis and pyruvate intolerance. Our findings suggest that nutrient-sensitive DSCR1-4 is a novel target for controlling hepatic gluconeogenesis in diabetes.

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Dual Role of CREB in The Regulation of VSMC Proliferation: Mode of Activation Determines Pro- or Anti-Mitogenic Function

Cited by 24 publications

References 52 publications

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

Ending Restenosis: Inhibition of Vascular Smooth Muscle Cell Proliferation by cAMP

A single extra copy of Down syndrome critical region 1–4 results in impaired hepatic glucose homeostasis

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