Cell division autoantigen 1 enhances signaling and the profibrotic effects of transforming growth factor-β in diabetic nephropathy

Tu, Yugang; Wu, Tieqiao; Dai, Aozhi; Pham, Yen; Chew, Phyllis; Wang, Yu; Toh, Ban‐Hock; Zhu, Hong; Cao, Zemin; Cooper, Mark E.; Chai, Zhonglin

doi:10.1038/ki.2010.374

Cited by 26 publications

(53 citation statements)

References 44 publications

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“…26 Consequently, safely blocking the pathologic actions or activities of TGF-b represents an important priority for the prevention and management of DN. In the present study, we show that genetic deletion of CDA1, a key enhancer of TGF-b expression and activity, 19,20 had no adverse effects on mouse health and attenuated the effects of diabetes on albuminuria, renal injury, and matrix accumulation in the kidney. When the cellular level of CDA1 is decreased by either genetic deletion, which was shown in this study, or siRNA knockdown, which was previously described, 19,20 TGF-b signaling is attenuated but not totally blocked.…”

Section: Discussionsupporting

confidence: 51%

“…In the present study, we show that genetic deletion of CDA1, a key enhancer of TGF-b expression and activity, 19,20 had no adverse effects on mouse health and attenuated the effects of diabetes on albuminuria, renal injury, and matrix accumulation in the kidney. When the cellular level of CDA1 is decreased by either genetic deletion, which was shown in this study, or siRNA knockdown, which was previously described, 19,20 TGF-b signaling is attenuated but not totally blocked. Thus, these findings strengthen the postulate that CDA1 is a potential molecular target to reduce the pathologic levels of TGF-b activity in diabetes, leading ultimately to retardation of DN.…”

Section: Discussionsupporting

confidence: 51%

“…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%

“…18 Our group has previously identified that the pathologic profibrotic effects of TGF-b in DN are, at least in part, mediated by enhanced TGF-b signaling modulated by cell division autoantigen 1 (CDA1). 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.…”

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confidence: 99%

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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

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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.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionsupporting

confidence: 51%

Section: Cda1 Deficiency Attenuates Tgf-b-associatedmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

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“…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

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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...

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TSPYL1 as a Critical Regulator of TGFβ Signaling through Repression of TGFBR1 and TSPYL2

Tan,

Miao,

Luo

et al. 2024

Advanced Science

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Nucleosome assembly proteins (NAPs) have been identified as histone chaperons. Testis‐Specific Protein, Y‐Encoded‐Like (TSPYL) is a newly arisen NAP family in mammals. TSPYL2 can be transcriptionally induced by DNA damage and TGFβ causing proliferation arrest. TSPYL1, another TSPYL family member, has been poorly characterized and is the only TSPYL family member known to be causal of a lethal recessive disease in humans. This study shows that TSPYL1 and TSPYL2 play an opposite role in TGFβ signaling. TSPYL1 partners with the transcription factor FOXA1 and histone methyltransferase EZH2, and at the same time represses TGFBR1 and epithelial‐mesenchymal transition (EMT). Depletion of TSPYL1 increases TGFBR1 expression, upregulates TGFβ signaling, and elevates the protein stability of TSPYL2. Intriguingly, TSPYL2 forms part of the SMAD2/3/4 signal transduction complex upon stimulation by TGFβ to execute the transcriptional responses. Depletion of TSPYL2 rescues the EMT phenotype of TSPYL1 knockdown in A549 lung carcinoma cells. The data demonstrates the prime role of TSPYL2 in causing the dramatic defects in TSPYL1 deficiency. An intricate counter‐balancing role of TSPYL1 and TSPYL2 in regulating TGFβ signaling is also unraveled.

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Cell division autoantigen 1 enhances signaling and the profibrotic effects of transforming growth factor-β in diabetic nephropathy

Cited by 26 publications

References 44 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

TSPYL1 as a Critical Regulator of TGFβ Signaling through Repression of TGFBR1 and TSPYL2

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