Cell division autoantigen 1 plays a profibrotic role by modulating downstream signalling of TGF-β in a murine diabetic model of atherosclerosis

Pham, Yen; Tu, Yugang; Wu, Tieqiao; Allen, Terri J.; Calkin, Anna C.; Watson, Anna; Li, Jiaze; Jandeleit‐Dahm, Karin; Toh, Ban‐Hock; Cao, Zemin; Cooper, Mark E.; Chai, Zhonglin

doi:10.1007/s00125-009-1555-9

Cited by 31 publications

(51 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…19 CDA1 knockdown by siRNA not only attenuates TGF-b-stimulated Smad3 (mothers against decapentaplegic homolog 3) phosphorylation and transcriptional activities but also ultimately blocks the stimulated expression of TGF-b target genes in association with fibrogenesis, such as connective tissue growth factor (CTGF), collagens, and fibronectin. 19,20 These findings support the hypothesis that CDA1 is a potential molecular target for retarding the pathologic activities of TGF-b and renal scarring in diabetes.…”

supporting

confidence: 71%

“…Signaling Pathways In Vivo Involving Smad3 and Extracellular Signal-Regulated Kinase MitogenActivated Protein Kinase in Mouse Kidney Because CDA1 seems to play a significant role in enhancing TGF-b signaling in vitro, 19,20 it was hypothesized that the diabetes-induced activation of TGF-b signaling pathways, including Smad3 and extracellular signal-regulated kinase 1/2(p44/42) [ERK1/2(p44/42)] mitogen-activated protein kinase, would be attenuated in CDA1 KO mice. To examine this postulate, we assessed the activated form of Smad3 in the kidneys of these mice by immunohistochemical staining using an antibody specific for phospho-Smad3 (Ser 423/425 ).…”

Section: Cda1 Deficiency Attenuates Tgf-b-associatedmentioning

confidence: 99%

See 1 more Smart Citation

Genetic Deletion of Cell Division Autoantigen 1 Retards Diabetes-Associated Renal Injury

Chai¹,

Dai²,

Tu³

et al. 2013

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Cell division autoantigen 1 (CDA1) enhances TGF-b signaling in renal and vascular cells, and renal expression of CDA1 is elevated in animal models of diabetes. In this study, we investigated the genetic deletion of Tspyl2, the gene encoding CDA1, in C57BL6 and ApoE knockout mice. The increased renal expression of TGF-b1, TGF-b type I and II receptors, and phosphorylated Smad3 associated with diabetes in wild-type mice was attenuated in diabetic CDA1 knockout mice. Notably, CDA1 deletion significantly reduced diabetes-associated renal matrix accumulation and immunohistochemical staining for collagens III and IV and attenuated glomerular and tubulointerstitial injury indices, despite the presence of persistent hyperglycemia, polyuria, renal hypertrophy, and hyperfiltration. Furthermore, CDA1 deletion reduced gene expression of TGF-b1 receptors in the kidney, resulting in a functionally attenuated response to exogenous TGF-b, including reduced levels of phosphorylated Smad3 and ERK1/2, in primary kidney cells from CDA1 knockout animals. Taken together, these data suggest that CDA1 deletion reduces but does not block renal TGF-b signaling. Because direct antagonism of TGF-b or its receptors has unwanted effects, CDA1 may be a potential therapeutic target for retarding DN and perhaps, other kidney diseases associated with TGF-b-mediated fibrogenesis.

show abstract

supporting

confidence: 71%

Section: Cda1 Deficiency Attenuates Tgf-b-associatedmentioning

confidence: 99%

Genetic Deletion of Cell Division Autoantigen 1 Retards Diabetes-Associated Renal Injury

Chai¹,

Dai²,

Tu³

et al. 2013

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…Since TSPYL2 had been associated with the pro-fibrotic role of TGFβ in diabetic atherosclerosis and diabetic retinopathy, [13][14][15] we tested whether TSPYL2 could affect TGFβ-driven phenotypes in our cancer cell systems. TGFβ is known to induce proliferation arrest in primary epithelial cells of various organs and the TGFβ pathway is frequently deregulated in malignancies.…”

Section: Resultsmentioning

confidence: 99%

TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation

et al. 2015

View full text Add to dashboard Cite

REST/NRSF is a transcriptional repressor of neuronal genes that has been implicated in development and cancer. In epithelial tissues, REST acts as a tumor suppressor and in breast cancer, loss of REST is associated with disease recurrence and poor prognosis. Here, we identify TSPYL2 (also known as CDA1 and DENTT) as a novel component of the REST protein complex. We show that REST and TSPYL2 are regulators of TGFβ signaling and that cell-cycle arrest induced by TGFβ requires both REST and TSPYL2. Importantly, knockdown of REST or TSPYL2 resulted in transformation of human mammary epithelial cells. Mechanistically, we demonstrate that the TSPYL2/REST complex promotes TGFβ signaling by repressing the expression of genes, such as the proto-oncogene neurotrophic tyrosine kinase receptor C (TrkC). These data provide insight into the role of REST as a tumor suppressor in epithelial tissues through the regulation of the TGFβ pathway. Cell Death and Differentiation (2015) 22, 1353-1362 doi:10.1038/cdd.2014; published online 23 January 2015The transcription factor REST was originally discovered as a repressor of neuronal differentiation genes in non-neuronal lineages. Therefore, REST is considered as a master regulator of neurogenesis in development and maintenance of gene silencing. [1][2][3][4] Recently, it has been recognized that aberrant REST function also has a role in human malignancies, largely depending on the cellular context. 5 Focal genomic deletions targeting the REST locus have been found in colon adenocarcinoma and REST protein expression is often lost in small cell lung carcinoma cells. 6,7 In breast cancer, the loss of full-length (FL) REST protein is associated with disease recurrence and poor prognosis.8 However, the underlying mechanism of how REST protects against transformation in epithelial tissues has remained largely elusive.We have previously implicated the testis-specific protein, Y-encoded-like (TSPY-L) family of genes in cancer by identifying TSPYL5 expression as a prognostic marker of poor clinical outcome in breast cancer.9 TSPYL5 can interfere with p53-dependent cell-cycle arrest and oncogene-induced senescence triggering p53 ubiquitination and protein degradation.9 Besides TSPYL5, the TSPYL family of genes includes several other members (four coding genes and one pseudogene) whose functions are still unknown. All five proteins (TSPYL1, TSPYL2, TSPYL4, TSPYL5, and TSPYL6) are characterized by a predicted nucleosome assembly protein (NAP) domain, although functional evidence of NAP activity has not been reported of any of the TSPYL family members. TSPYL2, which shares only partial homology with TSPYL5, has been proposed as a candidate tumor suppressor in carcinoma cells.10 TSPYL2 is a negative regulator of proliferation, induces p21 CDKN1A , and inhibits anchorageindependent growth; however, the mechanism through which TSPYL2 may function as a tumor suppressor is poorly understood. [10][11][12] In this study, we identify TSPYL2 as a component of the REST/NRSF transcriptional repressor comple...

show abstract

“…Catechin beneficially impacts many of these parameters including vascular dysfunction, including lipoprotein oxidation, blood platelet aggregation, vascular inflammation, vascular smooth muscle cell (VSMC) proliferation, altered lipid profile and vascular reactivity. Besides being antioxidants, catechins exert biological effects by modulating some cellular signaling pathways that lead to a reduction in inflammation, platelet aggregation, and an elevation of vascular reactivity [29]. The sources for the reactive oxygen species (ROS) production during CVD are uncoupling of mitochondrial electron transport, pro-inflammatory cytokines and induction of oxidative enzymes such as inducible nitric oxide synthase (iNOS) and xanthine oxidase (XO) [30].…”

Section: Introductionmentioning

confidence: 99%

“…The phenomena of endothelial dysfunction, mostly reduced availability of NO but also other factors, is widely associated with the pathogenesis and the precipitation of the clinical manifestations of CVDs. Experimental and clinical studies have shown that catechins improve endothelial function [29]. Quercetin is a naturally occurring flavonoid that exerts multiple pharmacological effects.…”

Section: Introductionmentioning

confidence: 99%

Honey-derived Flavonoids: Natural Products for the Prevention of Atherosclerosis and Cardiovascular Diseases

Afroz¹,

EM²,

Little³

2016

Clin Exp Pharmacol

View full text Add to dashboard Cite

The ancient product honey produced by honeybees, particularly the species Apis mellifera from the nectar blossoms or from exudates of trees and plants. Honey contains a very high content of carbohydrates, mostly monoand disaccharides but it also contains many members of the family of antioxidant flavonoids. Over the last several decade of studies on human disease processes it has become recognized that an elevated, unfavourable oxidation status and a states of chronic inflammation underlies multiple diseases most notably, cardiovascular disease (CVD). The underlying cause of most CVD is atherosclerosis, the trapping of lipids in the vessel wall by modified proteoglycans, followed by oxidation, a chronic immune response and the development and rupture of atherosclerotic plaques. Many of the flavonoids present in honey have actions which impact on the oxidative and other processes of atherosclerosis. In this review we describe the actions of many of the flavonoids present in honey and speculate on the manner in which these might aggregate to produce a favorable CVD protective effect of honey per se.

show abstract

Cell division autoantigen 1 plays a profibrotic role by modulating downstream signalling of TGF-β in a murine diabetic model of atherosclerosis

Cited by 31 publications

References 41 publications

Genetic Deletion of Cell Division Autoantigen 1 Retards Diabetes-Associated Renal Injury

Genetic Deletion of Cell Division Autoantigen 1 Retards Diabetes-Associated Renal Injury

TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation

Honey-derived Flavonoids: Natural Products for the Prevention of Atherosclerosis and Cardiovascular Diseases

Contact Info

Product

Resources

About