PYGB

Gene Summary

Gene:PYGB; glycogen phosphorylase B
Aliases: GPBB
Location:20p11.21
Summary:The protein encoded by this gene is a glycogen phosphorylase found predominantly in the brain. The encoded protein forms homodimers which can associate into homotetramers, the enzymatically active form of glycogen phosphorylase. The activity of this enzyme is positively regulated by AMP and negatively regulated by ATP, ADP, and glucose-6-phosphate. This enzyme catalyzes the rate-determining step in glycogen degradation. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:glycogen phosphorylase, brain form
Source:NCBIAccessed: 12 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 12 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Messenger RNA
  • Oligonucleotides, Antisense
  • Western Blotting
  • Cultured Cells
  • CRAF
  • Liver Cancer
  • Transfection
  • Glycogen
  • Phosphorylase Kinase
  • Apoptosis
  • Cancer Gene Expression Regulation
  • Northern Blotting
  • Breast Cancer
  • Oligonucleotide Array Sequence Analysis
  • Proteins
  • Protein Subunits
  • RTPCR
  • Stomach Cancer
  • Up-Regulation
  • KIAA1199 protein, human
  • Cell Survival
  • Chromosome 20
  • Gene Expression Profiling
Tag cloud generated 12 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PYGB (cancer-related)

Chen LA, Van Meerbeke S, Albesiano E, et al.
Fecal detection of enterotoxigenic Bacteroides fragilis.
Eur J Clin Microbiol Infect Dis. 2015; 34(9):1871-7 [PubMed] Free Access to Full Article Related Publications
Bacteroides fragilis is a common colonic symbiote of which one subtype, enterotoxigenic Bacteroides fragilis (ETBF), causes inflammatory diarrhea. However, asymptomatic ETBF colonization is common. Through its primary virulence factor, B. fragilis toxin (BFT), ETBF causes asymptomatic, chronic colitis in C57BL/6 mice and increased colon tumorigenesis in multiple intestinal neoplasia mice. Human studies suggest an association between ETBF infection, inflammatory bowel disease, and colon cancer. Additional studies on ETBF epidemiology are, therefore, crucial. The goal of this study is to develop a reliable fecal diagnostic for ETBF. To develop a sensitive assay for ETBF, we tested multiple protocols on mouse stools spiked with serially diluted ETBF. Each assay was based on either touchdown or quantitative polymerase chain reaction (qPCR) and used primers targeted to bft to detect ETBF. Using touchdown PCR or qPCR, the mean ETBF detection limit was 1.55 × 10(6) colony-forming units (CFU)/g stool and 1.33 × 10(4) CFU/g stool, respectively. Augmentation of Bacteroides spp. growth in fecal samples using PYGB (Peptone Yeast Glucose with Bile) broth enhanced ETBF detection to 2.93 × 10(2) CFU/g stool using the touchdown PCR method and 2.63 × 10(2) CFU/g stool using the qPCR method. Fecal testing using combined culture-based amplification and bft touchdown PCR is a sensitive assay for the detection of ETBF colonization and should be useful in studying the role of ETBF colonization in intestinal diseases, such as inflammatory bowel disease and colon cancer. We conclude that touchdown PCR with culture-based amplification may be the optimal ETBF detection strategy, as it performs as well as qPCR with culture-based amplification, but is a less expensive technique.

Song B, Park JC, Song WY
A low-complexity 2-point step size gradient projection method with selective function evaluations for smoothed total variation based CBCT reconstructions.
Phys Med Biol. 2014; 59(21):6565-82 [PubMed] Related Publications
The Barzilai-Borwein (BB) 2-point step size gradient method is receiving attention for accelerating Total Variation (TV) based CBCT reconstructions. In order to become truly viable for clinical applications, however, its convergence property needs to be properly addressed. We propose a novel fast converging gradient projection BB method that requires 'at most one function evaluation' in each iterative step. This Selective Function Evaluation method, referred to as GPBB-SFE in this paper, exhibits the desired convergence property when it is combined with a 'smoothed TV' or any other differentiable prior. This way, the proposed GPBB-SFE algorithm offers fast and guaranteed convergence to the desired 3DCBCT image with minimal computational complexity. We first applied this algorithm to a Shepp-Logan numerical phantom. We then applied to a CatPhan 600 physical phantom (The Phantom Laboratory, Salem, NY) and a clinically-treated head-and-neck patient, both acquired from the TrueBeam™ system (Varian Medical Systems, Palo Alto, CA). Furthermore, we accelerated the reconstruction by implementing the algorithm on NVIDIA GTX 480 GPU card. We first compared GPBB-SFE with three recently proposed BB-based CBCT reconstruction methods available in the literature using Shepp-Logan numerical phantom with 40 projections. It is found that GPBB-SFE shows either faster convergence speed/time or superior convergence property compared to existing BB-based algorithms. With the CatPhan 600 physical phantom, the GPBB-SFE algorithm requires only 3 function evaluations in 30 iterations and reconstructs the standard, 364-projection FDK reconstruction quality image using only 60 projections. We then applied the algorithm to a clinically-treated head-and-neck patient. It was observed that the GPBB-SFE algorithm requires only 18 function evaluations in 30 iterations. Compared with the FDK algorithm with 364 projections, the GPBB-SFE algorithm produces visibly equivalent quality CBCT image for the head-and-neck patient with only 180 projections, in 131.7 s, further supporting its clinical applicability.

Terashima M, Fujita Y, Togashi Y, et al.
KIAA1199 interacts with glycogen phosphorylase kinase β-subunit (PHKB) to promote glycogen breakdown and cancer cell survival.
Oncotarget. 2014; 5(16):7040-50 [PubMed] Free Access to Full Article Related Publications
The KIAA1199 gene was first discovered to be associated with non-syndromic hearing loss. Recently, several reports have shown that the up-regulation of KIAA1199 is associated with cancer cell migration or invasion and a poor prognosis. These findings indicate that KIAA1199 may be a novel target for cancer therapy. Therefore, we explored in detail the function of KIAA1199 in cancer cells. In this study, we investigated the interaction of KIAA1199 protein with intracellular proteins in cancer cells. To this end, we expressed KIAA1199-MBP fusion protein and performed a pull-down assay. In addition, KIAA1199-overexpressing cancer cell lines were constructed using a retroviral vector and were used for further experiments. A pull-down analysis showed that the glycogen phosphorylase kinase β-subunit (PHKB) interacted with the C-terminal region of KIAA1199 protein. Furthermore, we observed the interaction of KIAA1199 with glycogen phosphorylase brain form (PYGB) under serum-free conditions. The interaction promoted glycogen breakdown and cancer cell survival. Our findings indicate that KIAA1199 plays an important role in glycogen breakdown and cancer cell survival and that it may represent a novel target for cancer therapy.

Horacek JM, Jebavy L, Vasatova M, et al.
Glycogen phosphorylase BB as a potential marker of cardiac toxicity in patients treated with anthracyclines for acute leukemia.
Bratisl Lek Listy. 2013; 114(12):708-10 [PubMed] Related Publications
OBJECTIVES: The aim of the presented study was to assess plasma glycogen phosphorylase BB (GPBB) concentrations in acute leukemia patients treated with anthracycline containing chemotherapy.
BACKGROUND: Anthracyclines represent the highest risk for development of cardiotoxicity. GPBB belongs to proposed biomarkers of cardiac injury with a very limited experience in this context.
METHODS: Totally, 24 adult patients with acute leukemia were enrolled. Plasma GPBB concentrations were measured by ELISA at diagnosis (before chemotherapy), after first chemotherapy with anthracyclines and 6 months after the completion of treatment. The cut-off value for GPBB positivity was 10.00 µg/L as recommended by the manufacturer.
RESULTS: Before chemotherapy, the mean plasma GPBB concentration was 5.25±3.81 µg/L, increased above the cut-off in 1 patient (4.2 %). After the first chemotherapy, the mean GPBB was 6.61±5.54 µg/L, positive in 7 (29.2 %) patients. Six months after treatment, the mean GPBB was 10.06±11.41 µg/L, positive in 8 (33.3 %) patients. Six months after treatment, we found a significant correlation between elevation in GPBB and diastolic left ventricular dysfunction on echocardiography (r=0.621; p<0.0001). The differences in plasma GPBB between healthy blood donors and patients treated for acute leukemia were statistically significant (p<0.01 in all cases).
CONCLUSION: Our results suggested that GPBB could become a potential biomarker for detection of acute and chronic cardiotoxicity associated with anthracycline containing chemotherapy. The predictive value for development of treatment-related cardiomyopathy in future is not clear and will be evaluated during the follow-up. Further studies are needed to define the potential role of GPBB and other biomarkers in the assessment of chemotherapy-induced cardiotoxicity (Ref. 21). Text in PDF www.elis.sk.

Philips KB, Kurtoglu M, Leung HJ, et al.
Increased sensitivity to glucose starvation correlates with downregulation of glycogen phosphorylase isoform PYGB in tumor cell lines resistant to 2-deoxy-D-glucose.
Cancer Chemother Pharmacol. 2014; 73(2):349-61 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: As tumors evolve, they upregulate glucose metabolism while also encountering intermittent periods of glucose deprivation. Here, we investigate mechanisms by which pancreatic cancer cells respond to therapeutic (2-deoxy-D-glucose, 2-DG) and physiologic (glucose starvation, GS) forms of glucose restriction.
METHODS: From a tumor cell line (1420) that is unusually sensitive to 2-DG under normoxia, low (14DG2)- and high (14DG5)-dose resistant cell lines were selected and used to probe the metabolic pathways involved with their response to different forms of glucose deprivation.
RESULTS: Muted induction of the unfolded protein response was found to correlate with resistance to 2-DG. Additionally, 14DG2 displayed reduced 2-DG uptake, while 14DG5 was cross-resistant to tunicamycin, suggesting it has enhanced ability to manage glycosylation defects. Conversely, 2-DG-resistant cell lines were more sensitive than their parental cell line to GS, which coincided with lowered levels of glycogen phosphorylase (PYGB) and reduced breakdown of glycogen to glucose in the 2-DG-resistant cell lines. Moreover, by inhibiting PYGB in the parental cell line, sensitivity to GS was increased.
CONCLUSIONS: Overall, the data demonstrate that the manner in which glucose is restricted in tumor cells, i.e., therapeutic or physiologic, leads to differential biological responses involving distinct glucose metabolic pathways. Moreover, in evolving tumors where glucose restriction occurs, the identification of PYGB as a metabolic target may have clinical application.

Zhou DX, Zheng LY, Qu HX, et al.
Identification and differential expression of human carcinoma-associated antigens in hepatocellular carcinoma tissues.
Exp Biol Med (Maywood). 2013; 238(2):167-75 [PubMed] Related Publications
This study was designed to identify and verify hepatocellular carcinoma (HCC)-associated human carcinoma antigens (HCAs) that may be useful as tumor markers for HCC. We found that BCE075 and BCD021 anti-HCA antibodies were immunostained in the liver tissue samples and showed specific staining. Their expression was increased in HCC compared with normal liver tissues (P = 0.008). Immunoprecipitation and mass spectrometry analyses of the proteins precipitated by these two antibodies were identified to be cytoskeleton-associated protein 4 (CLIMP63) and brain-type glycogen phosphorylase (PYGB). This study demonstrated that HCC tissues expressed specific HCA glycoproteins, suggesting that our mouse monoclonal anti-HCA antibodies could be useful for immunohistochemical analysis of HCA expression as potential biomarkers for HCC diagnosis.

Horacek JM, Vasatova M, Tichy M, et al.
The use of cardiac biomarkers in detection of cardiotoxicity associated with conventional and high-dose chemotherapy for acute leukemia.
Exp Oncol. 2010; 32(2):97-9 [PubMed] Related Publications
AIM: Monitoring of cardiotoxicity of conventional and high-dose chemotherapy (HD-CT) with multiple biomarkers of cardiac injury - glycogen phosphorylase BB (GPBB), heart-type fatty acid binding protein (H-FABP), cardiac troponins (cTnT, cTnI), creatine kinase MB (CK-MB mass), myoglobin.
METHODS: A total of 47 adult acute leukemia patients were studied - 24 patients treated with conventional CT containing anthracyclines (ANT) and 23 patients treated with HD-CT (myeloablative preparative regimen) followed by hematopoietic cell transplantation (HCT). Cardiac biomarkers were assessed prior to treatment (before CT/HD-CT), after first CT with ANT, after last CT with ANT in the first group, after HD-CT and after HCT in the second group. Values above the reference range were considered elevated.
RESULTS: Before CT/HD-CT, all biomarkers of cardiac injury were below the cut-offs in all patients. GPBB increased above the cut-off (7.30 microg/L) in 4 (16.7%) patients after first CT and in 5 (20.8%) patients after last CT with ANT. GPBB increased above the cut-off in 5 (21.7%) patients after HD-CT and remained elevated in 5 (21.7%) patients after HCT. CTnI became elevated (above 0.40 microg/L) in 2 (8.3%) patients after first and last CT with ANT. Both patients with cTnI positivity had elevated GPBB. Other tested biomarkers remained below the cut-offs during the study.
CONCLUSION: Our results suggest that GPBB could become a sensitive biomarker for detection of acute cardiotoxicity associated with conventional CT containing ANT and HD-CT followed by HCT. The predictive value for development of cardiomyopathy in the future is not known and should be evaluated during a prospective follow-up. Based on our data, a larger prospective and multicenter study would be most desirable to define the potential role of new circulating biomarkers in the assessment of cardiotoxicity in oncology.

Horacek JM, Jebavy L, Ulrychova M, et al.
Glycogen phosphorylase BB could be a new biomarker for detection of cardiac toxicity during hematopoietic cell transplantation for hematological malignancies.
Bone Marrow Transplant. 2010; 45(6):1123-4 [PubMed] Related Publications

Horacek JM, Tichy M, Pudil R, et al.
Multimarker approach to evaluation of cardiac toxicity during preparative regimen and hematopoietic cell transplantation.
Neoplasma. 2008; 55(6):532-7 [PubMed] Related Publications
Cardiac toxicity of preparative regimen (PR) containing high-dose Cyclophosphamide (120 mg/kg) followed by hematopoietic cell transplantation (HCT) was evaluated with 6 biomarkers of cardiac injury: N-terminal pro brain natriuretic peptide (NT-proBNP), creatine kinase MB (CK-MB mass), cardiac troponins (cTnT, cTnI), heart-type fatty acid binding protein (H-FABP), glycogen phosphorylase BB (GPBB). Twenty-three patients (mean age 44.5+/-10.6 years, 15 males) with acute leukemia were studied. All biomarkers were measured the day before PR, the day after PR, the day after HCT and 14 days after HCT. We found NT-proBNP elevations above 500 ng/L in 6 (26.1 %) patients after PR, in 9 (39.1 %) after HCT and in 7 (30.4 %) 14 days after HCT. GPBB became elevated (above 7.30 microg/L) in 5 (21.7 %) patients after PR, remained elevated in 5 (21.7 %) after HCT and in 2 (8.7 %) 14 days after HCT. A significant correlation between elevation in NT-proBNP and GPBB was found. Other markers remained within the reference range early after PR and HCT. Our findings show that administration of PR and HCT for acute leukemia is associated with acute neurohumoral activation of cardiac dysfunction (significant rise in NT-proBNP) and may lead to GPBB elevation. These changes could indicate acute cardiac toxicity due to treatment and require further follow-up. The predictive value for development of cardiomyopathy in the future is unclear. Further studies will be needed to define the potential role of new biomarkers in this context.

Horacek JM, Tichy M, Pudil R, Jebavy L
Glycogen phosphorylase BB could be a new circulating biomarker for detection of anthracycline cardiotoxicity.
Ann Oncol. 2008; 19(9):1656-7 [PubMed] Related Publications

Horacek JM, Tichy M, Jebavy L, et al.
Use of multiple biomarkers for evaluation of anthracycline-induced cardiotoxicity in patients with acute myeloid leukemia.
Exp Oncol. 2008; 30(2):157-9 [PubMed] Related Publications
AIM: To assess cardiac toxicity of anthracycline treatment with six biomarkers of cardiac injury: myoglobin, creatine kinase MB (CK-MB mass), cardiac troponin T (cTnT), cardiac troponin I (cTnI), heart-type fatty acid binding protein (H-FABP), glycogen phosphorylase BB (GPBB).
METHODS: We evaluated anthracycline-induced cardiotoxicity in 12 acute myeloid leukemia patients (mean age 51.3-/+10.7 years, 7 females). All biomarkers were measured at the baseline, after first chemotherapy (CT) with anthracyclines, after last CT with anthracyclines (total cumulative dose 479.8-/+106.2 mg/m2) and 6 months thereafter. Values above the reference range were considered elevated.
RESULTS: GPBB increased above the cut-off (7.30 microg/L) in 2 (16.7%) patients after first CT, in 3 (25.0%) patients after last CT and remained elevated in 2 (16.7%) patients within 6 months after CT. CTnI became elevated (above 0.40 microg/L) in 1 (8.3%) patient after first and last CT and within 6 months after CT. CTnT remained negative (below 0.01 microg/L) during CT in all patients. Six months after CT, delayed cTnT positivity was found in 1 (8.3%) patient. All patients with cTnI or cTnT positivity had elevated GPBB. Other biomarkers (myoglobin, CK-MB mass, H-FABP) remained within the reference range in all patients.
CONCLUSION: Our preliminary results suggest that GPBB could be a new promising marker for detection of anthracycline-related cardiotoxicity and probably superior to cardiac troponins. The predictive value for development of cardiomyopathy in the future is not clear and will be evaluated during a prospective follow-up.

Lee MK, Kim JH, Lee CH, et al.
Clinicopathological significance of BGP expression in non-small-cell lung carcinoma: relationship with histological type, microvessel density and patients' survival.
Pathology. 2006; 38(6):555-60 [PubMed] Related Publications
AIMS: Brain-type glycogen phosphorylase (BGP) is the major isoform of glycogen phosphorylase found in fetal and neoplastic tissues, and is generally thought to induce glucose supply during an ischaemic period. This study was performed to investigate BGP expression in non-small-cell lung carcinoma (NSCLC).
METHODS: A total of 119 cases of NSCLC, including 63 squamous cell carcinomas (SqCCs) and 56 adenocarcinomas (ACs), were imunohistochemically evaluated for BGP expression, and its expression was correlated with clinicopathological parameters.
RESULTS: In total, 76.5% were positive, while non-neoplastic bronchial epithelial cells were weakly positive and pneumocytes were negative. High BGP expression was noted in 78.6% of ACs and 36.5% of SqCCs (p=0.001). Microvessel density was higher in the low BGP expression tumours (29.6 +/- 16.9/mm(2)) than in the high expression tumours (22.8+/-13.8/mm(2)) (p=0.017). BGP expression did not correlate with patient age or tumour stage, but was more frequent in females than males. Kaplan-Meier analysis showed that high BGP expression was associated with poorer survival (p=0.032).
CONCLUSIONS: BGP is expressed in NSCLC, particularly AC, and is an independent poor prognostic factor.

Mewani RR, Tian S, Li B, et al.
Gene expression profile by inhibiting Raf-1 protein kinase in breast cancer cells.
Int J Mol Med. 2006; 17(3):457-63 [PubMed] Related Publications
Raf-1 protein serine-threonine kinase plays an important role in cell growth, proliferation, and cell survival. Previously, we and others have demonstrated that antisense raf oligonucleotide-mediated inhibition of Raf-1 expression leads to tumor growth arrest, radiosensitization and chemosensitization in vivo. Raf-1 inhibition is also associated with apoptotic cell death. In this study, we inhibited Raf-1 using an antisense raf oligonucleotide (AS-raf-ODN) to identify downstream targets of Raf-1 using microarray gene expression analysis. Treatment of MDA-MB-231 breast cancer cells with 250 nM AS-raf-ODN led to significant inhibition of Raf-1 protein (75.2 +/- 9.6%) and c-raf-1 mRNA levels (86.2 +/- 3.3%) as compared to untreated control cells. The lipofectin control or mismatch oligonucleotide had no effect on Raf-1 expression. To determine the changes in gene expression profiles that were due to inhibition of Raf-1, we simultaneously compared the gene expression patterns in AS-raf-ODN treated cells with untreated control cells and cells treated with lipofectin alone or MM-ODN. A total of 17 genes (4 upregulated and 13 down-regulated) including c-raf-1 were identified that were altered after AS-raf-ODN treatment. Functional clustering analysis revealed genes involved in apoptosis (Bcl-XL), cell adhesion (paxillin, plectin, Rho GDIalpha, CCL5), metabolism (GM2A, SLC16A3, PYGB), signal transduction (protein kinase C nu), and transcriptional regulation (HMGA1), and membrane-associated genes (GNAS, SLC16A3). Real-time PCR, Northern analysis and Western analysis confirmed the microarray findings. Our study provides insight into Raf-1 related signaling pathways and a model system to identify potential target genes.

Tashima S, Shimada S, Yamaguchi K, et al.
Expression of brain-type glycogen phosphorylase is a potentially novel early biomarker in the carcinogenesis of human colorectal carcinomas.
Am J Gastroenterol. 2000; 95(1):255-63 [PubMed] Related Publications
OBJECTIVE: Our previous studies have demonstrated the significant role of brain-type glycogen phosphorylase (BGP) in the carcinogenesis of gastric carcinoma. The aims of the present study were to investigate the expression of BGP in colorectal carcinoma as well as the timing of this expression in the adenoma-carcinoma sequence (ACS), in comparison with the overexpression of p53 protein. We also sought to identify this marker in the particular colorectal mucosa bearing de novo carcinoma.
METHODS: The expression of BGP and p53 protein in colorectal carcinoma using affinity purified specific anti-human BGP antibody (Ab) and anti-p53 Ab was studied using 96 resected specimens. Further investigation to examine the timing of BGP expression in comparison with p53 overexpression was carried out using 13, 18, eight, and 16 specimens of adenoma with mild, moderate, and severe dysplasia, and carcinoma in adenoma, respectively. The BGP immunohistochemistry in whole resected human colorectal mucosa (two with carcinoma and one with ulcer) was carried out using specific anti-BGP and anti-p53 Ab.
RESULTS: The BGP visualized by immunohistochemistry was commonly present in colorectal carcinoma (83.3%). The expression of this molecule during ACS showed excellent correlation with the increased dysplasia and was found before p53 overexpression, whereas no BGP expression was seen in the normal human large intestine remote from the cancer foci. Positive staining in overtly normal-looking colonic mucosa was observed mainly around carcinomas without any adenoma component.
CONCLUSIONS: The present study is the first to localize the BGP molecule in colorectal carcinoma, adenoma, and normal mucosa. It is suggested that BGP is a novel biomarker for carcinogenesis in both the pathways of ACS and the de novo colorectal carcinoma.

Shimada S, Tashima S, Yamaguchi K, et al.
Carcinogenesis of intestinal-type gastric cancer and colorectal cancer is commonly accompanied by expression of brain (fetal)-type glycogen phosphorylase.
J Exp Clin Cancer Res. 1999; 18(1):111-8 [PubMed] Related Publications
Our previous studies have demonstrated the significant enzymatic activity of glycogen phosphorylase (GP) in the gastric carcinoma and proliferating cells of particular intestinal metaplasia (IM). This paper reviewed the identification of the GP isoform in the gastrointestinal carcinoma, and the investigation on the role of this molecule in the gastrointestinal carcinogenesis. The only isoform expressed in gastric cancer was brain-type GP (BGP) using polymerase chain reaction (PCR) analysis. The expression of BGP, oncogene products and proliferating cell nuclear antigen in the gastric and colorectal carcinomas, their premalignant lesions, and the normal mucosa were examined using 136 gastric and 96 colorectal surgically resected specimens, and 55 endoscopically resected colorectal adenomas. The BGP visualized by immunohistochemistry was commonly present in intestinal-type gastric (80.6%) and colorectal (83.3%) carcinomas, whereas no BGP expression was seen in the normal human gastric and large intestinal mucosa except in the BGP foci described below. IMs with BGP had close correlation with intestinal-type gastric carcinoma, and some of them coexpressed accumulated p53 protein. The expression of BGP during 'adenoma carcinoma sequence' (ACS) showed excellent correlation with the increased dysplasia and was found prior to p53 expression. Positive staining in overtly normal looking colonic mucosa (BGP foci) was observed mainly around carcinomas without any adenoma component, and frequent p53 mutation (41.2%) was detected in the BGP foci using PCR-single strand conformation polymorphism analysis. It is suggested that BGP is a novel biomarker for carcinogenesis in the intestinal-type gastric carcinoma and in both of the pathways of ACS and the 'de novo' colorectal carcinoma.

Uno K, Shimada S, Tsuruta J, et al.
Nuclear localization of brain-type glycogen phosphorylase in some gastrointestinal carcinoma.
Histochem J. 1998; 30(8):553-9 [PubMed] Related Publications
Our previous reports have demonstrated frequent and strong expression of glycogen phosphorylase (EC 2.4.1.1) activity mainly in the cytoplasm of gastric carcinoma. Although previous studies have suggested the phosphorylase glycosyltransferase system to be in the nucleus from enzyme histochemical analyses, intranuclear localization of the phosphorylase has not been fully established. The aims of the present study are to investigate the nuclear localization of glycogen phosphorylase and to identify the isoform of phosphorylase in the nucleus of gastrointestinal carcinoma. The activity of glycogen phosphorylase in carcinoma cells corresponding to the nucleus was demonstrated using enzyme cytochemical analysis. The phosphorylase activity coincided with localization revealed by immunocytochemistry using affinity-purified specific anti-human brain-type glycogen phosphorylase antibody. The isoform expressed in the nuclei of carcinoma cells was identified as being only the brain type according to a polymerase chain reaction-based assay using RNA obtained from gastric carcinoma cells and primers specific to muscle, liver and brain types of glycogen phosphorylase. The intranuclear localization of the brain-type isoform was confirmed by immunoelectron microscopical analyses. Further investigation to examine the nuclear localization in human carcinoma tissue (145 and 25 specimens with gastric and colonic carcinoma respectively) was carried out by immunohistochemistry using specific anti-brain-type antibody. Nuclear immunostaining was observed in seven cases out of 145 gastric carcinoma. The present study is the first to clarify the nuclear localization of glycogen phosphorylase with enzymatic activity in gastrointestinal carcinoma. The isoform of the enzyme expressed in the carcinoma was identified as the brain type. These results warrant further studies on the mechanisms for transporting the large molecule of brain-type glycogen phosphorylase to nuclei and its function in the nucleus of carcinoma cells.

Matsuzaki H, Shimada S, Uno K, et al.
Novel subtyping of intestinal metaplasia in the human stomach: brain-type glycogen phosphorylase expression in the proliferative zone and its relationship with carcinogenesis.
Am J Clin Pathol. 1998; 109(2):181-9 [PubMed] Related Publications
Although reports have suggested the incomplete type of intestinal metaplasia (IM) had a close correlation with carcinoma, considerable data showed no apparent relationship between the particular type of IM and the intestinal type carcinoma. The purpose of this study was to establish a novel classification of IM using brain-type glycogen phosphorylase (BGP) from a carcinogenetic viewpoint. The only isoform expressed in gastric cancer was BGP using polymerase chain reaction analysis. We studied 136 specimens with gastric carcinoma and the adjacent IM using specific anti-BGP antibody with its correlation to subtypes of IM, proliferating cell nuclear antigen-labeling index, and various oncogene products. Brain-type glycogen phosphorylase was expressed in 80.5% of the intestinal type and 18.8% of the diffuse type of carcinoma and in 87.5% and 41.6% in the generative zone of IM adjacent to cancer foci, respectively, whereas no reactivity was observed in the normal gastric mucosa. The proportion of the positivity in the cancer and IM was significantly greater in the intestinal-type carcinoma than in the diffuse type. The expression of BGP in the generative cells of IM had no significant correlation with the conventional type of IM. Intestinal metaplasias with BGP expression were significantly higher in a proliferating state than in those without BGP, and some of them that were coexpressed accumulated p53 in the generative cells. The relationship between IM with BGP in the generative cells and intestinal-type carcinoma was apparently closer than the conventional subtype of IM and gastric cancer. Intestinal-type carcinoma might arise from some of these proliferating cells with BGP.

Mayer D, Seelmann-Eggebert G, Letsch I
Glycogen phosphorylase isoenzymes from hepatoma 3924A and from a non-tumorigenic liver cell line. Comparison with the liver and brain enzymes.
Biochem J. 1992; 282 ( Pt 3):665-73 [PubMed] Free Access to Full Article Related Publications
Glycogen phosphorylase isoenzymes were isolated from normal rat liver, rat brain, the glycogen-poor Morris hepatoma (MH) 3924A, and the glycogen-rich non-tumorigenic liver cell line C1I. Electrophoretic and immunological characterization of the enzymes showed that tumour and C1I cells expressed a phosphorylase isoform similar to the brain type; the liver type was not detectable. All enzymes were obtained as dimers; the Mr of the subunits was 96,000 (liver), 93,000 (brain and MH 3924A) and 92,000 (C1I). Isoelectric focusing revealed a main band of pI 6.34 for liver phosphorylase a, pI 5.67 for the enzymes from MH 3924A and brain, and pI 5.68 for C1I phosphorylase. Partial kinetic characterization of the AMP-independent forms of the isoenzymes yielded Km values for glucose 1-phosphate of 3.5 +/- 0.5 mM (liver), 3.9 mM (brain), 1.9 +/- 0.3 mM (MH 3924A) and 2.5 +/- 0.5 mM (C1I); Km values for glycogen were 0.4 mM (liver) and 0.3 mM (MH 3924A and C1I), calculated as glucose equivalents. The AMP-independent phosphorylase was inhibited by glucose 6-phosphate (Glc6P) with Ki values of 0.32 +/- 0.03 mM (C1I), 0.50 +/- 0.04 mM (MH 3924A) and approximately 5 mM (brain). The inhibition could be abolished by 1 mM-AMP, indicating that AMP and Glc6P may partially compete for the same site on the protein. Liver phosphorylase a was not inhibited by up to 25 mM-Glc6P. In contrast with liver and brain isoenzymes, phosphorylase from the cell lines was not affected by NaF and Na2SO4. The data show that both the hepatocellular carcinoma and the non-malignant immortalized liver cells express a phosphorylase isoform different from the liver type. Furthermore, there is some evidence that the enzyme from MH 3924A and C1I cells is distinct from brain phosphorylase a, in spite of electrophoretic and immunological resemblance, and that this isoenzyme is subject to altered metabolic regulation.

Mayer D, Letsch I
Resolution of glycogen phosphorylase isoenzymes in precast PhastSystem polyacrylamide gels.
Electrophoresis. 1991; 12(4):297-302 [PubMed] Related Publications
Homogeneous (7.5%) and gradient (10-15%) ultrathin nondenaturating miniaturized polyacrylamide gels (Pharmacia PhastGel media) were used to separate glycogen phosphorylase isoforms from rabbit muscle, rat liver and brain, MH 3924A cells, a dedifferentiated hepatocellular carcinoma of the rat, and C1I cells, a nontumorigenic epithelial rat liver cell line. The enzymes were detected by in situ phosphorylase assay and by immunoblotting. Phosphorylase proteins from the brain, MH 3924A, and C1I exhibited similar electrophoretic mobility, which was different from that of the enzymes from the muscle and normal liver. Molecular weight determination from sodium dodecyl sulfate gels yielded similar data for the subunits of muscle and liver enzymes (98,000 and 96,000), respectively, on one hand, and brain, MH 3924A tumor, and nontumorigenic C1I cells (93,000, 93,000 and 92,000), respectively, on the other. In the native gels the enzymes migrated as dimers: for muscle phosphorylase a, a tetramer was also observed. The a and b forms of the enzymes could not be resolved. An antibody raised against rat liver phosphorylase reacted only with the liver enzyme, whereas an antibody raised against brain phosphorylase stained the brain enzyme and the enzymes from MH 3924A and C1I cells. This indicates that hepatoma cells and immortalized nontumorigenic epithelial liver cells express a phosphorylase isoenzyme that is different from the liver type but similar to the brain type. The PhastSystem provides a rapid, sensitive, and highly reproducible method to resolve the different isoenzymes of glycogen phosphorylase.

Takashi M, Koshikawa T, Kurobe N, Kato K
Elevated concentrations of brain-type glycogen phosphorylase in renal cell carcinoma.
Jpn J Cancer Res. 1989; 80(10):975-80 [PubMed] Related Publications
We determined tissue concentrations of brain-type glycogen phosphorylase in normal kidney and renal cell carcinoma by enzyme immunoassay; we also localized it immunohistochemically. Tissue concentration of brain-type glycogen phosphorylase in the renal cortex (n = 13) was 1430 +/- 709 ng/mg protein (mean +/- standard deviation) and that in the medulla (n = 13) was 1270 +/- 635 ng/mg protein. On the other hand, the concentration in renal cell carcinoma (n = 26) was 2530 +/- 1540 ng/mg protein, ranging from 520 to 6860 ng/mg, significantly higher than those in renal cortex and medulla. Clear cell type tumors contained slightly higher levels of the phosphorylase (2600 +/- 1430 ng/mg protein) than granular cell type tumors (2100 +/- 1520 ng/mg protein). In renal tissues, brain-type glycogen phosphorylase was immunohistochemically localized in epithelial cells of proximal and distal tubules, collecting tubules, thick and thin limbs of loops of Henle, and Bowman's capsules. In renal cell carcinoma, the phosphorylase was immunohistochemically demonstrated in 97% (34/35) of cases, including one sarcomatoid variant. These findings indicate that renal cell carcinoma cells contain enhanced tissue levels of brain-type glycogen phosphorylase.

Newgard CB, Littman DR, van Genderen C, et al.
Human brain glycogen phosphorylase. Cloning, sequence analysis, chromosomal mapping, tissue expression, and comparison with the human liver and muscle isozymes.
J Biol Chem. 1988; 263(8):3850-7 [PubMed] Related Publications
We have cloned the cDNA encoding a new isozyme of glycogen phosphorylase (1,4-D-glucan:orthosphosphate D-glucosyltransferase, EC 2.4.1.1) from a cDNA library prepared from a human brain astrocytoma cell line. Blot-hybridization analysis reveals that this message is preferentially expressed in human brain, but is also found at a low level in human fetal liver and adult liver and muscle tissues. Although previous studies have suggested that the major isozyme of phosphorylase found in all fetal tissues is the brain type, our data show that the predominant mRNA in fetal liver (24-week gestation) is the adult liver form. The protein sequence deduced from the nucleotide sequence of the brain phosphorylase cDNA is 862 amino acids long compared with 846 and 841 amino acids for the liver and muscle isozymes, respectively; the greater length of brain phosphorylase is entirely due to an extension at the far C-terminal portion of the protein. The muscle and brain isozymes share greater identity with regard to nucleotide and deduced amino acid sequences, codon usage, and nucleotide composition than either do with the liver sequence, suggesting a closer evolutionary relationship between them. Spot blot hybridization of the brain phosphorylase cDNA to laser-sorted human chromosome fractions, and Southern blot analysis of hamster/human hybrid cell line DNA reveals that the exact homolog of the newly cloned cDNA maps to chromosome 20, but that a slightly less homologous gene is found on chromosome 10 as well. The liver and muscle genes have previously been localized to chromosomes 14 and 11, respectively. This suggests that the phosphorylase genes evolved by duplication and translocation of a common ancestral gene, leading to divergence of elements controlling gene expression and of structural features of the phosphorylase proteins that confer tissue-specific functional properties.

Shimada S, Maeno M, Misumi A, et al.
Antigen reversion of glycogen phosphorylase isoenzyme in carcinoma and proliferative zone of intestinal metaplasia of the human stomach. An immunohistochemical study.
Gastroenterology. 1987; 93(1):35-40 [PubMed] Related Publications
Specific antibodies to three purified glycogen phosphorylase isoenzymes, i.e., brain (or fetal), muscle, and liver types, were used to study the localization of these isoenzymes in carcinoma and the proliferative zone of intestinal metaplasia of the human stomach. Both the malignant cells of well-differentiated adenocarcinoma and the proliferative zone of some intestinal metaplasia of the stomach were stained when the antibrain-type phosphorylase isoenzyme antibody was used, but not when the other two types were used. The results suggest that brain-type phosphorylase in gastric carcinoma could be one example of fetal protein expression in cancer, and that the proliferative zone of some intestinal metaplasia having brain-type phosphorylase may histogenetically relate to well-differentiated adenocarcinoma.

Satoh K, Imai F, Sato K
A new glycogen phosphorylase present in the rat tissues containing the brain-type isozyme. The active monomer of brain-type isozyme.
FEBS Lett. 1978; 95(2):239-42 [PubMed] Related Publications

Further References

Shimada S, Tashima S, Yamaguchi K, et al.
Carcinogenesis of intestinal-type gastric cancer and colorectal cancer is commonly accompanied by expression of brain (fetal)-type glycogen phosphorylase.
J Exp Clin Cancer Res. 1999; 18(1):111-8 [PubMed] Related Publications
Our previous studies have demonstrated the significant enzymatic activity of glycogen phosphorylase (GP) in the gastric carcinoma and proliferating cells of particular intestinal metaplasia (IM). This paper reviewed the identification of the GP isoform in the gastrointestinal carcinoma, and the investigation on the role of this molecule in the gastrointestinal carcinogenesis. The only isoform expressed in gastric cancer was brain-type GP (BGP) using polymerase chain reaction (PCR) analysis. The expression of BGP, oncogene products and proliferating cell nuclear antigen in the gastric and colorectal carcinomas, their premalignant lesions, and the normal mucosa were examined using 136 gastric and 96 colorectal surgically resected specimens, and 55 endoscopically resected colorectal adenomas. The BGP visualized by immunohistochemistry was commonly present in intestinal-type gastric (80.6%) and colorectal (83.3%) carcinomas, whereas no BGP expression was seen in the normal human gastric and large intestinal mucosa except in the BGP foci described below. IMs with BGP had close correlation with intestinal-type gastric carcinoma, and some of them coexpressed accumulated p53 protein. The expression of BGP during 'adenoma carcinoma sequence' (ACS) showed excellent correlation with the increased dysplasia and was found prior to p53 expression. Positive staining in overtly normal looking colonic mucosa (BGP foci) was observed mainly around carcinomas without any adenoma component, and frequent p53 mutation (41.2%) was detected in the BGP foci using PCR-single strand conformation polymorphism analysis. It is suggested that BGP is a novel biomarker for carcinogenesis in the intestinal-type gastric carcinoma and in both of the pathways of ACS and the 'de novo' colorectal carcinoma.

Uno K, Shimada S, Tsuruta J, et al.
Nuclear localization of brain-type glycogen phosphorylase in some gastrointestinal carcinoma.
Histochem J. 1998; 30(8):553-9 [PubMed] Related Publications
Our previous reports have demonstrated frequent and strong expression of glycogen phosphorylase (EC 2.4.1.1) activity mainly in the cytoplasm of gastric carcinoma. Although previous studies have suggested the phosphorylase glycosyltransferase system to be in the nucleus from enzyme histochemical analyses, intranuclear localization of the phosphorylase has not been fully established. The aims of the present study are to investigate the nuclear localization of glycogen phosphorylase and to identify the isoform of phosphorylase in the nucleus of gastrointestinal carcinoma. The activity of glycogen phosphorylase in carcinoma cells corresponding to the nucleus was demonstrated using enzyme cytochemical analysis. The phosphorylase activity coincided with localization revealed by immunocytochemistry using affinity-purified specific anti-human brain-type glycogen phosphorylase antibody. The isoform expressed in the nuclei of carcinoma cells was identified as being only the brain type according to a polymerase chain reaction-based assay using RNA obtained from gastric carcinoma cells and primers specific to muscle, liver and brain types of glycogen phosphorylase. The intranuclear localization of the brain-type isoform was confirmed by immunoelectron microscopical analyses. Further investigation to examine the nuclear localization in human carcinoma tissue (145 and 25 specimens with gastric and colonic carcinoma respectively) was carried out by immunohistochemistry using specific anti-brain-type antibody. Nuclear immunostaining was observed in seven cases out of 145 gastric carcinoma. The present study is the first to clarify the nuclear localization of glycogen phosphorylase with enzymatic activity in gastrointestinal carcinoma. The isoform of the enzyme expressed in the carcinoma was identified as the brain type. These results warrant further studies on the mechanisms for transporting the large molecule of brain-type glycogen phosphorylase to nuclei and its function in the nucleus of carcinoma cells.

Tashima S, Shimada S, Yamaguchi K, et al.
Expression of brain-type glycogen phosphorylase is a potentially novel early biomarker in the carcinogenesis of human colorectal carcinomas.
Am J Gastroenterol. 2000; 95(1):255-63 [PubMed] Related Publications
OBJECTIVE: Our previous studies have demonstrated the significant role of brain-type glycogen phosphorylase (BGP) in the carcinogenesis of gastric carcinoma. The aims of the present study were to investigate the expression of BGP in colorectal carcinoma as well as the timing of this expression in the adenoma-carcinoma sequence (ACS), in comparison with the overexpression of p53 protein. We also sought to identify this marker in the particular colorectal mucosa bearing de novo carcinoma.
METHODS: The expression of BGP and p53 protein in colorectal carcinoma using affinity purified specific anti-human BGP antibody (Ab) and anti-p53 Ab was studied using 96 resected specimens. Further investigation to examine the timing of BGP expression in comparison with p53 overexpression was carried out using 13, 18, eight, and 16 specimens of adenoma with mild, moderate, and severe dysplasia, and carcinoma in adenoma, respectively. The BGP immunohistochemistry in whole resected human colorectal mucosa (two with carcinoma and one with ulcer) was carried out using specific anti-BGP and anti-p53 Ab.
RESULTS: The BGP visualized by immunohistochemistry was commonly present in colorectal carcinoma (83.3%). The expression of this molecule during ACS showed excellent correlation with the increased dysplasia and was found before p53 overexpression, whereas no BGP expression was seen in the normal human large intestine remote from the cancer foci. Positive staining in overtly normal-looking colonic mucosa was observed mainly around carcinomas without any adenoma component.
CONCLUSIONS: The present study is the first to localize the BGP molecule in colorectal carcinoma, adenoma, and normal mucosa. It is suggested that BGP is a novel biomarker for carcinogenesis in both the pathways of ACS and the de novo colorectal carcinoma.

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