Role of Cell Division Autoantigen 1 (CDA1) in Cell Proliferation and Fibrosis

Toh, Ban Hock; Tu, Yugang; Cao, Zemin; Cooper, Mark E.; Chai, Zhonglin

doi:10.3390/genes1030335

Cited by 11 publications

(12 citation statements)

References 80 publications

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“…These results indicate that, alike CCAR2, TSPYL2 inhibits SIRT1 blocking its interaction with target proteins, as it was confirmed also by the analysis of p53-SIRT1 association in control and TSPYL2-depleted cells. Unfortunately, we were not able to test the effect of TSPYL2 overexpression on SIRT1 association with its targets because, as previously reported [11,18,19], ectopic expression of TSPYL2 arrests cell growth. However, it is also possible that TSPYL2 directly regulates p300 autoacetylation or the activity of other(s) acetyl-transferase(s) toward p300, through an unknown mechanism.…”

Section: Discussionmentioning

confidence: 98%

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TSPYL2 is a novel regulator of SIRT1 and p300 activity in response to DNA damage

et al. 2018

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Protein acetylation and deacetylation events are finely regulated by lysine-acetyl-transferases and lysine-deacetylases and constitute an important tool for the activation or inhibition of specific cellular pathways. One of the most important lysine-acetyl-transferases is p300, which is involved in the regulation of gene expression, cell growth, DNA repair, differentiation, apoptosis, and tumorigenesis. A well-known target of p300 is constituted by the tumor suppressor protein p53, which plays a critical role in the maintenance of genomic stability and whose activity is known to be controlled by post-translational modifications, among which acetylation. p300 activity toward p53 is negatively regulated by the NAD-dependent deacetylase SIRT1, which deacetylates p53 preventing its transcriptional activation and the induction of p53-dependent apoptosis. However, the mechanisms responsible for p53 regulation by p300 and SIRT1 are still poorly understood. Here we identify the nucleosome assembly protein TSPY-Like 2 (TSPYL2, also known as TSPX, DENTT, and CDA1) as a novel regulator of SIRT1 and p300 function. We demonstrate that, upon DNA damage, TSPYL2 inhibits SIRT1, disrupting its association with target proteins, and promotes p300 acetylation and activation, finally stimulating p53 acetylation and p53-dependent cell death. Indeed, in response to DNA damage, cells silenced for TSPYL2 were found to be defective in p53 activation and apoptosis induction and these events were shown to be dependent on SIRT1 and p300 function. Collectively, our results shed new light on the regulation of p53 acetylation and activation and reveal a novel TSPYL2 function with important implications in cancerogenesis.

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Section: Discussionmentioning

confidence: 98%

“…Testis-specific protein Y-encoded-like 2 (TSPYL2, also known as DENTT, CDA1, and TSPX) is an X-linked gene [11] encoding for a nuclear protein of the TSPY-L nucleosome assembly protein-1 superfamily, characterized by a predicted nucleosome assembly protein (NAP) domain for nucleosome remodeling and gene expression regulation [12].…”

Section: Introductionmentioning

confidence: 99%

TSPYL2 is a novel regulator of SIRT1 and p300 activity in response to DNA damage

et al. 2018

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“…Overexpression of TSPX retards cell proliferation and regulates the transition of both the G1 and G2 phases of the cell cycle 1431414243. It enhances the transforming growth factor-β (TGF-β) signaling in renal and vascular cells and increases the renal expression of TGF-β receptors and TGF-β-mediated fibrogenesis of the kidney in experimental models of diabetes 4143. Hence, TSPX could serve important functions in cell cycle regulation and cell proliferation and transcriptional functions and exert various effects on physiology and diseases involving these cellular properties.…”

Section: The Normal Functions Of Tspy and Tspx Genesmentioning

confidence: 99%

Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis

Lau

Kido

2019

Asian J Androl

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The Y-located testis-specific protein Y-encoded (TSPY) and its X-homologue TSPX originated from the same ancestral gene, but act as a proto-oncogene and a tumor suppressor gene, respectively. TSPY has specialized in male-specific functions, while TSPX has assumed the functions of the ancestral gene. Both TSPY and TSPX harbor a conserved SET/NAP domain, but are divergent at flanking structures. Specifically, TSPX contains a C-terminal acidic domain, absent in TSPY. They possess contrasting properties, in which TSPY and TSPX, respectively, accelerate and arrest cell proliferation, stimulate and inhibit cyclin B-CDK1 phosphorylation activities, have no effect and promote proteosomal degradation of the viral HBx oncoprotein, and exacerbate and repress androgen receptor (AR) and constitutively active AR variant, such as AR-V7, gene transactivation. The inhibitory domain has been mapped to the carboxyl acidic domain in TSPX, truncation of which results in an abbreviated TSPX exerting positive actions as TSPY. Transposition of the acidic domain to the C-terminus of TSPY results in an inhibitory protein as intact TSPX. Hence, genomic mutations/aberrant splicing events could generate TSPX proteins with truncated acidic domain and oncogenic properties as those for TSPY. Further, TSPY is upregulated by AR and AR-V7 in ligand-dependent and ligand-independent manners, respectively, suggesting the existence of a positive feedback loop between a Y-located proto-oncogene and male sex hormone/receptors, thereby amplifying the respective male oncogenic actions in human cancers and diseases. TSPX counteracts such positive feedback loop. Hence, TSPY and TSPX are homologues on the sex chromosomes that function at the two extremes of the human oncogenic spectrum.

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“…CDA1, encoded by TSPYL2 on the X chromosome, shares antiproliferative and profibrotic properties with TGF‐β. It inhibits cell growth through p53, pERK1/2 and p21‐mediated pathways, and is implicated in tumorigenesis and the DNA damage response 15 . Its profibrotic properties are mediated through cross‐talk with TGF‐β, which results in upregulation of extracellular matrix proteins.…”

Section: Cell Division Autoantigen 1 In Mediating Transforming Growthmentioning

confidence: 99%

“…This TGF‐β signaling through Smad3, which can also be activated by other stimuli, such as angiotensin II, regulates ECM production. Schema of TGF‐β induction of tissue fibrosis has been reviewed elsewhere 15 .…”

Section: Cell Division Autoantigen 1 In Mediating Transforming Growthmentioning

confidence: 99%

Pathogenesis of diabetic nephropathy

Cao

Cooper²

2011

Journal of Diabetes Investigation

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170

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As the increasing prevalence of diabetes reaches epidemic proportions worldwide, diabetic nephropathy and associated end‐stage renal failure will be an unavoidable major health burden to not only individuals with diabetes and their families, but also to the health systems both in developed and developing countries. Over the past decade, a large body of research has focused on diabetic nephropathy ranging from studies in molecular signaling, hemodynamic regulation and pharmaceutical intervention to clinical outcomes. It is likely that the pathophysiology of diabetic nephropathy involves a multifactorial interaction between metabolic and hemodynamic factors. Metabolic factors involve glucose‐dependent pathways, such as advanced glycation end‐products and their receptors. Hemodynamic factors include various vasoactive hormones, such as components of the renin–angiotensin system. It is likely that these metabolic and hemodynamic factors interact through shared molecular and signaling pathways, such as nuclear factor kappa‐light‐chain‐enhancer of activated B cells and protein kinase C with associated reactive oxygen species generation. It is likely that these contributing factors cause pathological damage not only to the glomerulus, in particular podocytes, but also to the tubulointerstitium. Specific inhibitors of the various pathways are now available and these emerging pharmaceutical interventions might have potential implications for the prevention and treatment of diabetic nephropathy. The mainstay of therapy remains the achievement of optimal glycemic and blood pressure control in order to slow the progression of diabetic nephropathy. Agents that interrupt the renin–angiotensin system have been shown to be particularly useful as renoprotective agents in both hypertensive and normotensive type 1 and type 2 diabetic subjects. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00131.x, 2011)

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Role of Cell Division Autoantigen 1 (CDA1) in Cell Proliferation and Fibrosis

Cited by 11 publications

References 80 publications

TSPYL2 is a novel regulator of SIRT1 and p300 activity in response to DNA damage

TSPYL2 is a novel regulator of SIRT1 and p300 activity in response to DNA damage

Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis

Pathogenesis of diabetic nephropathy

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