<i>TSP50</i> Encodes a Testis-Specific Protease and Is Negatively Regulated by <i>p53</i>

Xu, Haopeng; Shan, Jidong; Jurukovski, Vladimir; Yuan, Liming; Li, Jianhua; Tian, Kegui

doi:10.1158/0008-5472.can-06-3688

Cited by 42 publications

(43 citation statements)

References 45 publications

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“…As the TSP50 gene, which was negatively regulated by p53, was available in our lab, we cotransfected pGL/TSP50P (pGL containing the TSP50 promoter) with pcDNA/P53, in parallel, into MCF7/WT and HEK293 cells. The results clearly showed that p53 downregulated the TSP50 promoter (Xu et al, 2007), whereas it upregulated the WTH3 promoter. Similar results were obtained when MCF7/AdrR and Hela cells were used as hosts (data not shown), which suggested that WTH3 was upregulated by the p53 gene in a celltype independent manner.…”

Section: Resultsmentioning

confidence: 92%

WTH3 is a direct target of the p53 protein

Tian

Wang

2007

Br J Cancer

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Previous results showed that overexpression of the WTH3 gene in multidrug resistance (MDR) cells reduced MDR1 gene expression and converted their resistance to sensitivity to various anticancer drugs. The WTH3 gene promoter was found to be differentially regulated in paired MDR vs non-MDR MCF7 cells owing to epigenetic modifications and transcription factor modulations. To understand further the mechanisms that govern WTH3's differential expression, we uncovered a p53-binding site in its promoter, which indicated that WTH3 could be regulated by the p53 gene. This hypothesis was then tested by different strategies. The resulting data revealed that (1) the WTH3 promoter was upregulated by the p53 transgene in diverse host cells; (2) there was a correlation between WTH3 expression levels and p53 gene status in a cell line panel; (3) a WTH3 promoter region was directly targeted by the p53 protein in vitro and in vivo. In addition, overexpression of the WTH3 gene promoted the apoptotic phenotype in host cells. On the basis of these findings, we believe that the negative role played by the WTH3 gene in MDR development is through its proapoptotic potential that is regulated by multiple mechanisms at the transcription level, and one of these mechanisms is linked to the p53 gene.

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Section: Resultsmentioning

confidence: 92%

WTH3 is a direct target of the p53 protein

Tian

Wang

2007

Br J Cancer

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“…TSP50 is a testis-specific protease which is known to be a cancer testis antigen (47,59). The expression is regulated in part by methylation of the promoter (22), is negatively regulated by p53 (56), and is abnormally activated in a high proportion of breast cancers (59). The third gene, Gal3st1, which encodes CST, showed the greatest reduction in transcripts in BORIS Ϫ/Ϫ testis (Table 2).…”

Section: Targeted Disruption Of the Boris Genementioning

confidence: 99%

Expression of a Testis-Specific Form of Gal3st1 (CST), a Gene Essential for Spermatogenesis, Is Regulated by the CTCF Paralogous Gene BORIS

Suzuki

Kosaka-Suzuki

Pack

et al. 2010

Molecular and Cellular Biology

107

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Previously, it was shown that the CTCF paralogous gene, BORIS (brother of the regulator of imprinted sites) is expressed in male germ cells, but its function in spermatogenesis has not been defined. To develop an understanding of the functional activities of BORIS, we generated BORIS knockout (KO) mice. Mice homozygous for the null allele had a defect in spermatogenesis that resulted in small testes associated with increased cell death. The defect was evident as early as postnatal day 21 and was manifested by delayed production of haploid cells. By gene expression profiling, we found that transcript levels for Gal3st1 (also known as cerebroside sulfotransferase [CST]), known to play a crucial role in meiosis, were dramatically reduced in BORIS KO testes. We found that CST is expressed in testis as a novel testis-specific isoform, CST form F TS , that has a short exon 1f. We showed that BORIS bound to and activated the promoter of CST form F TS . Mutation of the BORIS binding site in the promoter reduced the ability of BORIS to activate the promoter. These findings define transcriptional regulation of CST expression as a critical role for BORIS in spermatogenesis.

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“…Although the physiologic function of TSP50 is not clarified, the characteristic of its expression makes it interesting as a potential target for cancer immunotherapy. Recent publications suggested that expression of TSP50 is regulated by CpG methylation of the promoter (35), similar to many other CTAs, and by various transcription factors including SP1, CCAAT/enhancer binding protein (C/EBP), and TP53 (36,37). However, none of these factors was shown to regulate expression of TSP50 in a physiological context, which make it unclear which factors are involved in vivo.…”

Section: Ctcfmentioning

confidence: 99%

Transcription Factor BORIS (Brother of the Regulator of Imprinted Sites) Directly Induces Expression of a Cancer-Testis Antigen, TSP50, through Regulated Binding of BORIS to the Promoter

Kosaka-Suzuki¹,

Suzuki²,

Pugacheva

et al. 2011

Journal of Biological Chemistry

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Cancer-testis antigens (CTAs) are normally expressed in testis but are aberrantly expressed in a variety of cancers with varying frequency. More than 100 proteins have been identified as CTA including testes-specific protease 50 (TSP50) and the testis-specific paralogue of CCCTC-binding factor, BORIS (brother of the regulator of imprinted sites). Because many CTAs are considered as excellent targets for tumor immunotherapy, understanding the regulatory mechanisms governing their expression is important. In this study we demonstrate that BORIS is directly responsible for the transcriptional activation of TSP50. We found two BORIS binding sites in the TSP50 promoter that are highly conserved between mouse and human. Mutations of the binding sites resulted in loss of BORIS binding and the ability of BORIS to activate the promoter. However, although expression of BORIS was essential, it was not sufficient for high expression of TSP50 in cancer cells. Further studies showed that binding of BORIS to the target sites was methylation-independent but was diminished by nucleosomal occupancy consistent with the findings that high expression of TSP50 was associated with increased DNase I sensitivity and high BORIS occupancy of the promoter. These findings indicate that BORIS-induced expression of TSP50 is governed by accessibility and binding of BORIS to the promoter. To our knowledge this is the first report of regulated expression of one CTA by another to be validated in a physiological context.

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TSP50 Encodes a Testis-Specific Protease and Is Negatively Regulated by p53

Cited by 42 publications

References 45 publications

WTH3 is a direct target of the p53 protein

WTH3 is a direct target of the p53 protein

Expression of a Testis-Specific Form of Gal3st1 (CST), a Gene Essential for Spermatogenesis, Is Regulated by the CTCF Paralogous Gene BORIS

Transcription Factor BORIS (Brother of the Regulator of Imprinted Sites) Directly Induces Expression of a Cancer-Testis Antigen, TSP50, through Regulated Binding of BORIS to the Promoter

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