Differential alternative splicing of human transglutaminase 4 in benign prostate hyperplasia and prostate cancer

Cho, Sung Yup; Choi, Kyung Ho; Jeon, Ju Hong; Kim, Chai Wan; Shin, Dong Myung; Lee, Jong Bouk; Lee, Sang Eun; Kim, Choung Soo; Park, Jeong‐Soo; Jeong, Eui Man; Jang, Geupil; Song, Kye Yong; Kim, In Gyu

doi:10.3858/emm.2010.42.4.031

Cited by 24 publications

(18 citation statements)

References 31 publications

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“…1c). Alternative splicing of exon 3 has been described by us and others for several TG genes including TG2, TG4, TG5 and band 4.2 protein and results in a TG with an altered N -terminal β-sandwich domain (Cohen et al 1993; Aeschlimann et al 1998; Candi et al 2001; Cho et al 2010; AK295775 in GenBank™). TG5 lacking exon 3 has no transamidase activity (Candi et al 2001).…”

Section: Resultsmentioning

confidence: 91%

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Transglutaminase 6: a protein associated with central nervous system development and motor function

et al. 2011

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Transglutaminases (TG) form a family of enzymes that catalyse various post-translational modifications of glutamine residues in proteins and peptides including intra- and intermolecular isopeptide bond formation, esterification and deamidation. We have characterized a novel member of the mammalian TG family, TG6, which is expressed in a human carcinoma cell line with neuronal characteristics and in mouse brain. Besides full-length protein, alternative splicing results in a short variant lacking the second β-barrel domain in man and a variant with truncated β-sandwich domain in mouse. Biochemical data show that TG6 is allosterically regulated by Ca2+ and guanine nucleotides. Molecular modelling indicates that TG6 could have Ca2+ and GDP-binding sites related to those of TG3 and TG2, respectively. Localization of mRNA and protein in the mouse identified abundant expression of TG6 in the central nervous system. Analysis of its temporal and spatial pattern of induction in mouse development indicates an association with neurogenesis. Neuronal expression of TG6 was confirmed by double-labelling of mouse forebrain cells with cell type-specific markers. Induction of differentiation in mouse Neuro 2a cells with NGF or dibutyryl cAMP is associated with an upregulation of TG6 expression. Familial ataxia has recently been linked to mutations in the TGM6 gene. Autoantibodies to TG6 were identified in immune-mediated ataxia in patients with gluten sensitivity. These findings suggest a critical role for TG6 in cortical and cerebellar neurons.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-011-1091-z) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 91%

“…c Schematic illustrating the relationship between gene organization and protein structure in the TG family. TG4 contains an additional exon, exon 1B, within intron 1 (Cho et al 2010) that can differentially be spliced in and encodes 45 amino acids. The band 4.2L variant contains an extended exon 1 ( hatched box ) (Sung et al 1992).…”

Section: Resultsmentioning

confidence: 99%

Transglutaminase 6: a protein associated with central nervous system development and motor function

et al. 2011

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“…Prostate diseases, such as prostate cancer, BPH, and prostatitis, present unique phenotypes at the level of their respective prostasomal proteomes. Some of these proteins have already been tested as potential biomarkers of prostate cancer [6,7,8].…”

Section: Discussionmentioning

confidence: 99%

“…revealed that some protein components of prostasomes could be promising candidates as diagnostic biomarkers for prostate diseases [6,7,8]. Among these proteins, prostatic exosomal protein (PSEP) is thought to be a potential marker of CP and was evaluated in this study.…”

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confidence: 99%

Clinical Evaluation of Urine Prostatic Exosomal Protein in the Diagnosis of Chronic Prostatitis

Li¹,

Jiang²,

Liu³

et al. 2017

Urol Int

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Objective: To evaluate the clinical potential of urine prostatic exosomal protein (PSEP) as a diagnostic biomarker of chronic prostatitis (CP). Materials andmethods: Using an enzyme-linked immunosorbent assay kit, urine PSEP levels were detected in 103 control cases as well as 283 cases of CP, with 82 cases fulfilling the definition of the USA National Institutes of Health category II (NIH-II), 108 cases of NIH-IIIa and 93 cases of NIH-IIIb. The values of age, body mass index, prostate volume, serum prostatic specific antigen (PSA) urine PSEP levels, and seminal parameters were analyzed. Results: The PSEP levels were significantly higher in patients of NIH-II (2.09 [2.35] ng/mL), NIH-IIIa (1.80 [2.95] ng/mL) and NIH-IIIb (1.64 [2.48] ng/mL) compared to the value of 0.24 (0.76) ng/mL in the controls. ROC identified a cutoff value of 1.387 ng/mL, with a sensitivity of 59.0% and specificity of 94.2%. The area under the ROC curve was 0.833. PSEP levels positively correlated with serum PSA levels in the NIH-IIIb group, and with EPS WBC count in the NIH-IIIa group, and with semen WBC count in each CP subgroups but negatively correlated with sperm motility in both the NIH-IIIa group and the NIH-IIIb group. Conclusion: Urine PSEP could be a potential biomarker for CP.

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“…TGM4 was previously suggested as a prostate cancer biomarker, but results were inconsistent and revealed either significant over-expression 65 or under-expression [66][67][68][69] of TGM4 in PCa versus benign disease, or inconclusive results with the opposite directions based on different assays 70 . TGM4 was found down-regulated 1.7-fold in urinary extracellular vesicles of PCa and had AUC 0.58 to diagnose PCa on biopsy 66 .…”

Section: Cc-by-nc-mentioning

confidence: 99%

Multi-omics biomarker pipeline reveals elevated levels of protein-glutamine gamma-glutamyltransferase 4 in seminal plasma of prostate cancer patients

Drabovich

Saraon

Drabovich³

et al. 2017

Preprint

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Prostate-specific antigen, a widely used biomarker of prostate cancer, lacks specificity and prognostic significance, which often results in over-diagnosis and over-treatment of prostate cancer. In this study, we investigated if seminal plasma proteins could increase specificity of detecting primary prostate cancer and discriminate between low-and high-grade cancers. To select 148 most promising biomarker candidates, we combined transcripts or proteins identified through five independent data mining or experimental approaches: tissue transcriptomics, seminal plasma proteomics, cell secretomics, tissue specificity and androgen regulation. To follow up these candidates, we designed a rigorous biomarker verification and validation pipeline based on multiplex quantitative selected reaction monitoring assays. We verified 77 and validated 19 most promising proteins in seminal plasma of 67 negative biopsy and 152 prostate cancer patients. Validation revealed a prostate-specific, secreted and androgen-regulated protein-glutamine gamma-glutamyltransferase 4 (TGM4), which could predict prostate cancer on biopsy and outperformed age and serum PSA. In the independent validation set re-measured by an in-house ELISA, TGM4 was significantly up-regulated (3.7-fold, P=0.005) and revealed AUC 0.66 for differentiating between negative biopsy and prostate cancer in patients with age ≥50 and blood serum PSA ≥4 ng/mL. Interestingly, none of validated biomarkers could differentiate between low-and high-grade cancers. Very low levels of TGM4 (120 pg/mL) were detected by ELISA in blood serum, but could not differentiate between negative biopsy, prostate cancer or prostate inflammation. Significantly higher levels of TGM4 in blood serum (3.5-fold, P = 0.0004) were found for younger men (<40 y.o.) relative to older men (≥70 y.o.). Our work may represent one of the most comprehensive studies on prostate cancer biomarkers in seminal plasma. Even though moderate performance of TGM4 as a single biomarker will unlikely result in its immediate use in the clinic, TGM4 may be further investigated in the distinct subtypes of prostate cancer and included into emerging multibiomarker panels.

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Differential alternative splicing of human transglutaminase 4 in benign prostate hyperplasia and prostate cancer

Cited by 24 publications

References 31 publications

Transglutaminase 6: a protein associated with central nervous system development and motor function

Transglutaminase 6: a protein associated with central nervous system development and motor function

Clinical Evaluation of Urine Prostatic Exosomal Protein in the Diagnosis of Chronic Prostatitis

Multi-omics biomarker pipeline reveals elevated levels of protein-glutamine gamma-glutamyltransferase 4 in seminal plasma of prostate cancer patients

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