Dual inhibition of Src family kinases and Aurora kinases by SU6656 modulates CTGF (connective tissue growth factor) expression in an ERK-dependent manner

Cicha, Iwona; Zitzmann, Rita; Goppelt‐Struebe, Margarete

doi:10.1016/j.biocel.2013.11.014

Cited by 5 publications

(4 citation statements)

References 33 publications

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“…In human ascending aortic aneurysms, increased reactive oxygen species (ROS) accumulation correlates with media layer degeneration and increased CTGF expression, which modulate the synthetic VSMC phenotype[50]. In addition, CTGF is also involved in monocyte migration and adhesion to injured vessel wall[50, 51]. Our findings are consistent with the previous studies and suggest that CTGF protein is overexpressed in the progression of AAA and correlates with synthetic SMCs[50, 62].…”

Section: Discussionsupporting

confidence: 87%

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Smooth muscle cell-specific Notch1 haploinsufficiency restricts the progression of abdominal aortic aneurysm by modulating CTGF expression

et al. 2017

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AimsInfiltration of macrophages and apoptosis of vascular smooth muscle cells (VSMCs) promote the development of abdominal aortic aneurysm (AAA). Previously, we demonstrated that global Notch1 deficiency prevents the formation of AAA in a mouse model. Herein, we sought to explore the cell-specific roles of Notch1 in AAA development.Methods and resultsCell-specific Notch1 haploinsufficient mice, generated on Apoe-/- background using Cre-lox technology, were infused with angiotensin II (1000 ng/min/kg) for 28 days. Notch1 haploinsufficiency in myeloid cells (n = 9) prevented the formation of AAA attributed to decreased inflammation. Haploinsufficiency of Notch1 in SMCs (n = 14) per se did not prevent AAA formation, but histoarchitectural traits of AAA including elastin degradation and aortic remodeling, were minimal in SMC-Notch1+/-;Apoe-/- mice compared to Apoe-/- mice (n = 33). Increased immunostaining of the contractile SMC-phenotype markers and concomitant decreased expression of synthetic SMC-phenotype markers were observed in the aortae of SMC-Notch1+/-;Apoe-/- mice. Expression of connective tissue growth factor (CTGF), a matrix-associated protein that modulates the synthetic VSMC phenotype, increased in the abdominal aorta of Apoe-/- mice and in the adventitial region of the abdominal aorta in human AAA. Notch1 haploinsufficiency decreased the expression of Ctgf in the aorta and in vitro cell culture system. In vitro studies on SMCs using the Notch1 intracellular domain (NICD) plasmid, dominant negative mastermind-like (dnMAML), or specific siRNA suggest that Notch1, not Notch3, directly modulates the expression of CTGF.ConclusionsOur data suggest that lack of Notch1 in SMCs limits dilation of the abdominal aorta by maintaining contractile SMC-phenotype and preventing matrix-remodeling.

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Section: Discussionsupporting

confidence: 87%

“…Connective tissue growth factor (CTGF), secreted by synthetic VSMCs and fibroblasts, is a potent ECM–inducing growth factor involved in regulating aneurysm-associated vascular remodeling[50, 51]. We examined if Notch1 haploinsufficiency in SMCs is associated with alterations in Ctgf expression.…”

Section: Resultsmentioning

confidence: 99%

Smooth muscle cell-specific Notch1 haploinsufficiency restricts the progression of abdominal aortic aneurysm by modulating CTGF expression

et al. 2017

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“…Overexpression of caRhoA not only increased F-actin fibers but also reduced attachment of the cells, implicating alterations of cell-cell contacts. This may also modulate Src activity [ 28 ], which has been shown earlier to regulate CTGF in HKC-8 cells [ 29 ]. Corresponding data were obtained by down-regulation of RhoA by siRNA, which strongly reduced basal and LPA-stimulated CTGF synthesis supporting the notion of an actin-dependent regulation of CTGF.…”

Section: Discussionmentioning

confidence: 99%

Actin-Mediated Gene Expression Depends on RhoA and Rac1 Signaling in Proximal Tubular Epithelial Cells

et al. 2015

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Morphological alterations of cells can lead to modulation of gene expression. An essential link is the MKL1-dependent activation of serum response factor (SRF), which translates changes in the ratio of G- and F-actin into mRNA transcription. SRF activation is only partially characterized in non-transformed epithelial cells. Therefore, the impact of GTPases of the Rho family and changes in F-actin structures were analyzed in renal proximal tubular epithelial cells. Activation of SRF signaling was compared to the regulation of a known MKL1/SRF target gene, connective tissue growth factor (CTGF). In the human proximal tubular cell line HKC-8 overexpression of two actin mutants either favoring or preventing the formation of F-actin fibers regulated SRF-mediated transcription as well as CTGF expression. Only overexpression of constitutively active RhoA activated SRF-dependent gene expression whereas no effect was detected upon overexpression of Rac1 mutants. To elucidate the functional role of Rho kinases as downstream mediators of RhoA, pharmacological inhibition and genetic inhibition by transient siRNA knock down were compared. Upon stimulation with lysophosphatidic acid (LPA) Rho kinase inhibitors partially suppressed SRF-mediated transcription, whereas interference with Rho kinase expression by siRNA reduced activation of SRF, but barely affected CTGF expression. Together with the partial inhibition of CTGF expression by the pharmacological inhibitors Y27432 and H1154, Rho kinases seem to be less important in mediating RhoA signaling related to CTGF expression in HKC-8 epithelial cells. Short term pharmacological inhibition of Rac1 activity by EHT1864 reduced SRF-dependent CTGF expression in HKC-8 cells, but was overcome by a stimulatory effect after prolonged incubation after 4-6 h. Similarly, human primary cells of proximal but not of distal tubular origin showed inhibitory as well as stimulatory effects of Rac1 inhibition. Thus, RhoA signaling activates MKL1-SRF-mediated CTGF expression in proximal tubular cells, whereas Rac1 signaling is more complex with adaptive cellular responses.

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“…What’s more, inhibition of Src kinases increased autophagy flux and reduced liver fibrosis ( Seo et al, 2020 ). SU6656, a dual inhibitor of Src family and Aurora kinases, reduced CTGF expression by inhibiting Src kinases in non-transformed epithelial cells ( Cicha et al, 2014 ). As a member of SFK, Fyn was activated in the liver of patients with fibrosis and knockdown Fyn with siRNA or gene knockout significantly prevented the activation of HSCs and reduced fibrosis in CCl 4 -induced mice.…”

Section: Progress In the Treatment Of Liver Fibrosismentioning

confidence: 99%

Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy

Tan

Sun

Xue

et al. 2021

Front. Cell Dev. Biol.

130

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Liver fibrosis is an abnormal wound repair response caused by a variety of chronic liver injuries, which is characterized by over-deposition of diffuse extracellular matrix (ECM) and anomalous hyperplasia of connective tissue, and it may further develop into liver cirrhosis, liver failure or liver cancer. To date, chronic liver diseases accompanied with liver fibrosis have caused significant morbidity and mortality in the world with increasing tendency. Although early liver fibrosis has been reported to be reversible, the detailed mechanism of reversing liver fibrosis is still unclear and there is lack of an effective treatment for liver fibrosis. Thus, it is still a top priority for the research and development of anti-fibrosis drugs. In recent years, many strategies have emerged as crucial means to inhibit the occurrence and development of liver fibrosis including anti-inflammation and liver protection, inhibition of hepatic stellate cells (HSCs) activation and proliferation, reduction of ECM overproduction and acceleration of ECM degradation. Moreover, gene therapy has been proved to be a promising anti-fibrosis method. Here, we provide an overview of the relevant targets and drugs under development. We aim to classify and summarize their potential roles in treatment of liver fibrosis, and discuss the challenges and development of anti-fibrosis drugs.

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Dual inhibition of Src family kinases and Aurora kinases by SU6656 modulates CTGF (connective tissue growth factor) expression in an ERK-dependent manner

Cited by 5 publications

References 33 publications

Smooth muscle cell-specific Notch1 haploinsufficiency restricts the progression of abdominal aortic aneurysm by modulating CTGF expression

Smooth muscle cell-specific Notch1 haploinsufficiency restricts the progression of abdominal aortic aneurysm by modulating CTGF expression

Actin-Mediated Gene Expression Depends on RhoA and Rac1 Signaling in Proximal Tubular Epithelial Cells

Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy

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