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PubMed2004

A reappraisal of the Rb1 gene abnormalities in the diagnosis of parathyroid cancer.

OBJECTIVES: Some histological features may suggest the malignant nature of a parathyroid tumour. However, the diagnosis of parathyroid cancer can only be definitively established in the presence of local invasion or metastases. DESIGN: We further investigated the role of the retinoblastoma gene (Rb1) and the breast cancer susceptibility gene (BRCA2) in the differential diagnosis between benign and malignant parathyroid tumours by evaluating loss of heterozygosity (LOH) at these loci and Rb protein (pRb) immunohistochemistry. PATIENTS AND MEASUREMENTS: Fifty-three parathyroid adenomas from patients with sporadic primary hyperparathyroidism (PHPT) and 10 parathyroid cancer specimens were studied. Microsatellite polymorphisms at the Rb1 and BRCA2 loci were polymerase chain reaction (PCR) amplified from each patient's paired tumour and leucocyte DNA samples, using oligonucleotide primers flanking the repeat sequence. Immunohistochemical staining of pRb was carried out using a monoclonal antibody. RESULTS: All but one of the 53 tumour-leucocyte pairs was informative for at least one of the three polymorphic markers of the Rb1 gene. Fifteen adenomas (28.8%) showed LOH. Regarding the BRCA2 gene, 46 tumour-leucocyte pairs were informative and LOH was present in eight (17.4%). All six carcinomas had LOH for at least one marker at the Rb1 locus. LOH for the BRCA2 microsatellite was found in three of the five informative primary tumour samples. Immunohistochemical analysis revealed that all adenomas were positive and the number of pRb-positive cells varied significantly among different samples. The mean percentage of stained cells was 15.7%. Eleven of the 30 (36.7%) adenomas showed sparse positive staining, 13 (43.3%) intermediate staining and six (20%) extensive staining. All parathyroid cancers were entirely negative for pRb immunostaining. CONCLUSIONS: Inactivation of the Rb1 gene is a common event in parathyroid tumorigenesis. Retention of heterozygosity seems to exclude parathyroid malignancy, which is suggested by the combined finding of LOH and lack of protein expression.

Adenoma↗

PubMed2001

Purification and characterization of ginsenoside Rb1-metabolizing beta-glucosidase from Fusobacterium K-60, a human intestinal anaerobic bacterium.

Fusobacterium K-60, a ginsenoside Rb1-metabolizing bacterium, was isolated from human intestinal feces. From this Fusodobacterium K-60, a ginsenoside Rb1-metabolizing enzyme, beta-glucosidase, has been purified. The enzyme was purified to apparent homogeneity by a combination of butyl-Toyopearl, hydroxyapatite ultragel, Q-Sepharose, and Sephacryl S-300 HR column chromatographies with a final specific activity of 1.52 micromol/min/mg. It had optimal activity at pH 7.0 and 40 degrees C. The molecular mass of this purified enzyme was 320 kDa, with 4 identical subunits (80 kDa). The purified enzyme activity was inhibited by Ba++, Fe++, and some agents that modify cysteine residues. This enzyme strongly hydrolyzed sophorose, followed by p-nitrophenyl beta-D-glucopyranoside, esculin, and ginsenoside Rb1. However, this enzyme did not change 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (IH-901) to 20(S)-protopanaxadiol, while it weakly changed ginsenoside Rb1 to IH-901. These findings suggest that the Fusobacterial beta-glucosidase is a novel enzyme transforming ginsenoside Rb1.

Fusobacterium↗

PubMed2000

The RB1 gene is the target of chromosome 13 deletions in malignant fibrous histiocytoma.

Forty-four malignant fibrous histiocytomas (MFHs) were studied by comparative genomic hybridization. Among the observed imbalances, losses of the 13q14-q21 region were observed in almost all tumors (78%), suggesting that a gene localized in this region could act as a tumor suppressor gene and that its inactivation could be relevant for MFH oncogenesis and/or progression. We determined by CA repeat analyses a consensus region of deletion focusing on the RB1 region. The RB1 gene was then analyzed by protein truncation test, direct sequencing, fluorescence in situ hybridization, Southern blotting, and immunohistochemistry. RB1 mutations and/or homozygous deletions were found in 7 of the 34 tumors analyzed (20%). Among the 35 tumors with comparative genomic hybridization imbalances analyzed by immunohistochemistry, 30 (86%) did not exhibit significant nuclear labeling. The high correlation between chromosome 13 losses and absence of RB1 protein expression and the mutations detected strongly suggest that RB1 gene inactivation is a pivotal event in MFH oncogenesis. Moreover, the observation of a high incidence of MFH in patients previously treated for hereditary retinoblastoma fits well this hypothesis.

Allelic Imbalance↗

PubMedDate not supplied

[RB1 and CDKN2A functional defects resulting in retinoblastoma].

Multiplex methylation-sensitive PCR was employed in studying the methylation of the RB1 and CDKN2A/p16 promoter regions in 52 retinoblastomas. Aberrant methylation inactivating RB1 was detected in 14 (27%) tumors. Methylation of p16 was for the first time observed in retinoblastoma (9 tumors, 17%). Both promoters proved to be methylated in two tumors. In four tumors, aberrant methylation was combined with structural defects of both RB1 alleles. Aberrant methylation of the p16 promoter was the second mutation event in two tumors and was not accompanied by RB1 defects in one tumor. Complex testing for RB1 mutations, loss of heterozygosity, and functional inactivation of the two genes revealed a molecular defect in at least one allele in 51 (98%) tumors.

Cyclin-Dependent Kinase Inhibitor p16↗

PubMed2001

[Effects of Ginsenosides Rg1 and Rb1 on Proliferation of Human Marrow Granulocyte-Macrophage Progenitor Cells]

Ginseng is a traditional Chinese medicine which has been used in treating anemia for thousands of years. It is composed of a lot of components. The main component is total saponin of panax ginseng (TSPG), which contains more than 20 ginsenosides including Rg1, Rb1 and so on. Previous studies have reported that total saponin of panax ginseng could promote hematopoiesis by stimulating proliferation of human erythroid grogenitor cells CFU-E and BFU-E, however, it had different effects on CFU-GM reported by various laboratories. In this study, CFU-GM assay was adopted to observe the ginsenosides Rg1 and Rb1's effects on the proliferation of human marrow grannulocyte-macrophage progenitor cells. The results showed that Rg1 and Rb1 had obvious promotive effect on the proliferation of CFU-GM, and the increasing rates of colony formation were up to (70.6 +/- 6.8)% and (65.1 +/- 6.3)%, respectively. There was no inhibiting effect on CFU-GM in high concentrations of Rg1 and Rb1. It is suggested that Rg1 and Rb1 can stimulate the proliferation of human granulocyte-macrophage progentors. The results of TSPG's various effects on CFU-GM might be caused by different contents of ginsenosides in TSPG used in different laboratories.

Journal Article↗

PubMedDate not supplied

Expression of ras Rb1 and p53 proteins in human breast cancer.

The ras, Rb and p53 genes have been implicated in the development of human breast cancer. Qualitative or quantitative changes in the expression of the ras p21 may lead to cell transformation, and this has been previously demonstrated in breast cancer. Both the retinoblastoma protein (Rb1) and the p53 gene product appear to function as negative regulators of cell division. We have investigated the expression of ras p21, Rb1 and p53 proteins in human breast cancer patients immunohistochemically, and correlated the results with a range of clinical and pathological parameters. Ras p21 expression was elevated in 65 per cent and p53 in 23 per cent of cases. Rb1 was expressed in 58 per cent of breast cancer tissues and in 75 per cent of normal tissue. Only four patients were found to have loss of Rb1 expression and also overexpression of both p53 and ras gene products. No correlations were found between the expression of these three genes and menopausal status, histological types or tumour grade. However, a correlation was found between Rb1 loss of expression and tumour diameter (greater than 2 cms), and no lymph node metastasis. Also, a significantly higher number of p53 staining specimens were found to be overexpressing the ras gene. These results suggest that all three oncogenes are most likely involved in the development of breast cancer but that their role is complex.

Animals↗

PubMed2005

[Effects of ginsenoside Rb1 on mouse embryonic development in vitro].

OBJECTIVE: To evaluate the developmental toxicity of ginsenoside Rb1 and the potential mechanism of it in vitro. METHODS: Whole embryo culture system was used in this research. Embryos were exposed to various concentrations of ginsenoside Rb1, and scored for growth and development at the end of the 48h culture period. RESULTS: With the concentration of Rb1 rising, the total morphological scores significantly decreased; Developments of forebrain, midbrain and optic system were relatively sensitive to Rb1 and were affected at the concentration of 30 microg/ml; hindbrain, Branchial arch and limb buds were affected at 50 microg/ml; Yolk sac was affected at the low concentration of 15 microg/ml and the indexes of embryonic growth and development decreased at the high concentration of 50 microg/ml. Moreover, the rate of embryo teratogenicity were obviously increased. CONCLUSION: Ginsenoside Rb1 displayed teratogenic action in mice. The damage on structure and function of yolk sac might be part of teratogenic mechanisms of it.

Abnormalities, Drug-Induced↗

PubMed1991

Anti-lipid peroxilative effect of ginsenoside Rb1 and Rg1.

It has been reported that Ginsenoside can increase body resistance to many harmful factors and protect tissues from damage when an organism is in stress. To understand the mechanism of this action, a study on the antioxidative effect of Ginsenoside Rb1 and Rg1 was carried out. Results showed that Ginsenoside Rb1 and Rg1 could inhibit lipid peroxidation of rat liver and brain microsomes and that Rb1, at the final concentration of 10(-4)-10(-3) mol/L, could scavenge O2-. induced by liver microsome-NADPH-gossypol system. In in vivo experiment, Rb1, at a dose of 50 and 25 mg/kg/day x 3 ip, inhibited MDA formation in liver homogenate of rats by 26.8% (P less than 0.05) and increased the activities of catalase and GSH peroxidase by 47.2% (P less than 0.001) and 96.4% (P less than 0.001), respectively. However, no change in the activity of superoxide dismutase was found in liver cytosol of rats treated with Rb1.

Aging↗

PubMed1989

Binding of the Rb1 protein to E1A products is required for adenovirus transformation.

Several cellular proteins, including polypeptides of 300, 107 and 105kDa, associate with the products of the E1A gene of adenovirus type 5. Here we show that the 105kDa species is the product of the recessive oncogene Rb1 which is absent or altered in retinoblastomas and other human cancers. About 75% of the total Rb1 protein in infected human KB cells was found to be complexed with E1A products and these data support the hypothesis that E1A-mediated transformation results from the elimination of functional Rb1 protein within the cell. However, while the interaction of E1A products with this cellular protein is necessary, transformation appears also to require binding of the 300 and 107kDa polypeptides. We also found that both the Rb1 protein and the 107kDa E1A-binding species were undetectable in a retinoblastoma cell line lacking both alleles of the Rb1 gene. These data suggest that the absence of both the 107kDa and 105kDa/Rb1 proteins may be involved in the development of the oncogenic phenotype of retinoblastoma cells.

Adenovirus Early Proteins↗

PubMed1989

The expression of the retinoblastoma gene product Rb1 in primary and adenovirus-transformed human cells.

Polyclonal antibodies to the human retinoblastoma gene product (Rb1) have been produced in rats by immunisation with a fusion protein comprising part of Rb1 together with the E. coli beta-Gal sequence. We have used these antibodies in Western blotting studies to screen a number of human foetal tissues and organs and found approximately similar levels of expression of Rb1 in all of them. The protein seems to be somewhat more abundant in some cell lines produced by transfection of human embryo retinal (HER) cells with adenovirus 12 early region 1 (Ad 12 E1), Ad 5 E1, Ad 2 E1A + mutant N-ras or SV40 DNA. Using co-immunoprecipitation followed by Western blotting we have shown that the Rb1 protein binds to Ad 12 E1A 266 and 235 amino acid proteins. This interaction is ionic strength dependent but is unaffected by non-ionic detergent up to a concentration of at least 1%. In Ad 12 infected human cells it appears that less E1A is bound to Rb1 than in the transformants. These results are discussed in view of the known similarities and differences between the amino acid sequences of Ad 12 and Ad 5 E1A proteins.

Adenoviruses, Human↗

PubMed1994

[Studies on the pharmacodynamics of ginsenoside-Rg1, -Rb1 and -Rb2 in rats].

The pharmacodynamics of ginsenoside-Rg1 (Rg1), -Rb1 (Rb1) and -Rb2 (Rb2) in rats were studied. In these studies, obvious differences were found in their pharmacodynamics. That is, Rg1 was easily hydrated to the same prospogenins in both rat stomach and 0.1 N HCl solution, but Rb1 and Rb2 were little decomposed (metabolised) in rat stomach and a small quantity of their hydroperoxide derivatives were found, but they were easily hydrated to their prosapogenins by 0.1 N HCl. These ginsenosides were decomposed (metabolised) to several prosapogenins by enteric bacteria and enteric enzymes. The modes of their decomposition (metabolism) were respectively different. In particular, the terminal sugar moiety at the C-20 hydroxy group was noted to affect the rates of their decomposition. The amount of Rg1 and Rb1 absorbed from the gastrointestinal tract of rat were 1.9% and 0.1% of the dose, respectively. And that of Rb2 was determined to be 3.7% of the dose by using 3H-labeled Rb2. Rg1 was excreted into the urine and bile in a 2:5 ratio. Rb1 and Rb2 were mainly excreted into the urine.

Administration, Oral↗

PubMed1996

A novel mutation in the promotor region in a family with a mild form of retinoblastoma indicates the location of a new regulatory domain for the RB1 gene.

We describe a family segregating the retinoblastoma phenotype where the affected individuals have only unifocal tumours and where linkage analysis has identified unaffected mutant gene carriers. DNA from members of this 'low penetrance' pedigree was subjected to an exon-by-exon SSCP analysis of the RB1 gene. No mutations were found in the 27 exons of the coding region but an SSCP band shift was seen for PCR products covering the RB1 promoter region. Sequencing identified a G-->C change within a GGGCGG motif which is the core of the recognition sequence of the SP1 transcription factor. Electromobility shift assays demonstrated that SP1 does not bind to oligomers from this region of the RB1 promoter but bandshifts were seen for an, as yet, unidentified protein(s) which was not seen using an oligomer containing the G-->C mutation. Thus, identification of a naturally occurring mutation in a family with only 'mild' phenotypes has identified another regulatory sequence in the RB1 promoter which binds an endogenous cellular protein(s). Identification of this protein should allow a better understanding of the control of expression of the RB1 gene.

Base Sequence↗

PubMed1995

[Protective effects of ginsenoside Rb1 and Rg1 on cultured hippocampal neurons].

It has been well documented that ginsenoside Rb1 and Rg1 are important active principles of ginseng. In the present studies, Rb1 and Rg1 were found to prolong the duration of neuronal life and provided partial protection against the excitotoxic effect of glutamate in primary hippocampal cultures. Since excitotoxic neuronal injury of glutamate is considered to be caused by the increase of intracellular Ca2+ concentrations, the effects of Rb1 and Rg1 on [Ca2+]i elevated by glutamate were measured in cultured hippocampal cells using Fura-2/AM as a calcium indicator. The results showed that Rb1 and Rg1 could selectively inhibit the high level glutamate (500 mumol.L-1) induced increase of [Ca2+]i, suggesting that the neuroprotective activities of Rb1 and Rg1 were mediated by blocking calcium over-influx into neuronal cells.

Animals↗

PubMed1996

RB1 oncosuppressor gene over-expression inhibits tumor progression and induces melanogenesis in metastatic melanoma cells.

The retinoblastoma gene (RB1) is frequently deleted or mutated in many tumor types and in all cases of retinoblastoma. Apart from its role in regulation of the cell cycle, the RB1 gene product (p110RB1) appears to be involved in control of differentiation. Malignant metastatic cells show many properties of poorly differentiated cells, and are highly invasive in vitro and in vivo. We have transfected the human RB1 cDNA in an expression vector under the control of the beta-actin promoter into B16F10 murine melanoma cells. These cells highly overexpress RB1 mRNA and the p110RB1 product, show reduced growth rate and increased melanogenesis in vitro. Vector control transfectants showed no alteration of invasiveness. The p110RB1 over-expressing cells also had a reduced capacity to migrate and invade through an artificial basement membrane, key characteristics of metastatic cells. When injected into nude mice, the p110RB1 over-expressing cells showed reduced tumor growth and reduced metastatic potential. The few metastasis observed were predominantly melanotic. These data indicate that RB1 gene expression is involved in melanoma cell differentiation and plays a role in downregulation of migration, invasion and metastatic potential of these cells.

Animals↗

PubMed1998

Molecular cytogenetic analysis in splenic lymphoma with villous lymphocytes: frequent allelic imbalance of the RB1 gene but not the D13S25 locus on chromosome 13q14.

Structural abnormalities of chromosome 13q are one of the most frequent genetic aberrations in human tumors. 13q rearrangements are, however, infrequent in splenic lymphoma with villous lymphocytes (SLVL) by karyotype analysis. We have investigated the incidence of 13q14 deletions in a series of 74 SLVL cases by interphase fluorescence in situ hybridization using unique sequence probes for the RB1 and the D13S25 loci, which are frequently deleted in chronic lymphocytic leukemia. Chromosome 12 was also evaluated by fluorescence in situ hybridization using a pericentromeric DNA probe. 13q14 deletion was detected in 37 of 74 (50%) tumors. Thirty-five cases (47%) exhibited monoallelic loss of RB1, and 9 (12%) showed hemizygous D13S25 deletion. Seven cases displayed coexistence of RB1 and D13S25 deletion. Trisomy 12 was detected in 2 of 74 (3%) tumors. G-banding analysis in 40 tumors showed no interstitial deletion of 13q14 in any case. In contrast with the molecular findings observed in chronic lymphocytic leukemia, our results indicate that trisomy 12 is an uncommon chromosomal aberration in SLVLs, and microdeletion of 13q14 at the RB1 locus but not D13S25 is a frequent and specific genetic event in this disease, suggesting that allelic loss of the RB1 gene may play a role in the pathogenesis of SLVL.

Aged↗

PubMed1998

Ginsenosides Rb1 and Rg3 protect cultured rat cortical cells from glutamate-induced neurodegeneration.

Certain natural products and Asian herbal remedies have been used in Asia to attenuate neurodegenerative diseases, including senile dementia. We have examined derivatives of several natural products for potential neuroprotective activity in an in vitro test system. In the present study, we assayed a number of compounds that were isolated from Panax ginseng C.A. Meyer (Araliaceae) for an ability to protect rat cortical cell cultures from the deleterious effects of the neurotoxicant, glutamate. We found that ginsenosides Rb1 and Rg3 significantly attenuated glutamate-induced neurotoxicity. Brief exposure of cultures to excess glutamate caused extensive neuronal death. Glutamate-induced neuronal cell damage was reduced significantly by pretreatment with Rb1 and Rg3. Ginsenosides Rb1 and Rg3 inhibited the overproduction of nitric oxide, which routinely follows glutamate neurotoxicity, and preserved the level of superoxide dismutase in glutamate-treated cells. Furthermore, in cultures treated with glutamate, these ginsenosides inhibited the formation of malondialdehyde, a compound that is produced during lipid peroxidation, and diminished the influx of calcium. These results show that ginsenosides Rb1 and Rg3 exerted significant neuroprotective effects on cultured cortical cells. Therefore, these compounds may be efficacious in protecting neurons from oxidative damage that is produced by exposure to excess glutamate.

Animals↗

PubMed2004

Retinoblastoma, pinealoma, and mild overgrowth in a boy with a deletion of RB1 and neighbor genes on chromosome 13q14.

We report on a 10-year-old boy with a normal karyotype and a chromosome 13q14 deletion of the retinoblastoma gene (RB1) by fluorescence in situ hybridization (FISH). He showed subtle signs of overgrowth, including macrocephaly, hepatomegaly, and inguinal hernia. The boy also had cryptorchism and mild developmental delay. In his first months of life, variant Wiedemann-Beckwith syndrome was tentatively suspected and he was included in a careful tumor prevention program. At the age of 11 months, bifocal retinoblastoma of the left eye was diagnosed. Pinealoma was suspected at the age of 19 months and was removed by neurosurgery at the age of 29 months. At 4 years and 4 months, the deletion of the RB1 gene was suspected on clinical grounds and was diagnosed by FISH and molecular studies. At that time, he was a near-normal healthy playful kindergarten child, height 107 cm (-0.3 SD), OFC 52.5 cm (+0.8 SD), developmental age 3-3.5 years. The combination of retinoblastoma, pinealoma, and deletion of the RB1 gene diagnosed by FISH has not been reported previously. The deletion spans at least 370-420 kb in size and is predicted to include proximal and distal neighbor genes. This report may assist in establishing the clinical signs of the contiguous gene syndrome at the RB1 locus on 13q14.

Brain Neoplasms↗

PubMed2002

Neuroprotective effects of ginseng total saponin and ginsenosides Rb1 and Rg1 on spinal cord neurons in vitro.

Spinal cord injury is a major cause of disability and results in many serious physical, psychological, and social difficulties. Numerous studies have shown that traumatic spinal cord injuries (SCI) lead to neuronal loss and axonal degeneration in and around the injury site that cause partial disability or complete paralysis. An important strategy in the treatment of SCI is to promote neuron survival and axon outgrowth, making possible the recovery of neural connections. Using an in vitro survival assay, we have identified ginsenosides Rb1 and Rg1, extracted from ginseng root (Panax ginseng C. A. Meyer), as efficient neuroprotective agents for spinal cord neurons. These compounds protect spinal neurons from excitotoxicity induced by glutamate and kainic acid, as well as oxidative stress induced by H(2)O(2). The neuroprotective effects are dose-dependent. The optimal doses are 20-40 microM for ginsenosides Rb1 and Rg1. The effects are specific for Rb1 and Rg1, since a third ginsenoside, Re, did not exhibit any activity. Ginseng has been used for thousands of years in the treatment of neurological disorders and other diseases in Asia. Ginsenosides Rb1 and Rg1 represent potentially effective therapeutic agents for spinal cord injuries.

Animals↗