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PubMed1998

Molecular analysis of the retinoblastoma (RB1) gene in acute myeloid leukemia patients.

The pathogenesis of acute leukemia is still poorly understood. In the past few years several groups have reported deletion of the RB1 gene or altered pRB expression in certain hematologic malignancies, suggesting a possible role of RB1 gene inactivation in the process of leukemogenesis. Most studies regarding structural abnormalities of the RB1 gene indicate that gross deletions or rearrangements are present in a small percentage of patients with acute myeloid leukemia (AML), as is the case with retinoblastoma, where the majority of RB1 gene abnormalities are attributed to point mutations. To investigate if such point mutations in the RB1 gene may have a role in leukemogenesis in AML, we screened the RB1 gene of 36 AML patients using conformation-sensitive gel electrophoresis (CSGE). No point mutations were found in the 27 exons, their flanking intron regions or in the promoter region in any of the 36 patients. Thus, according to our findings, the susceptibility in these patients for developing AML does not appear to be related to point mutations in the RB1 gene. While screening for point mutations, we identified a number of new and previously noted neutral sequence variations indicating the efficiency and sensitivity of CSGE in identifying small changes in the RB1 gene.

Adolescent↗

PubMed2004

Methylation status of RB1 promoter in Indian retinoblastoma patients.

Retinoblastoma can arise due to mutational inactivation or methylation of RB1 gene promoter. A 600-bp CpG island consisting of the essential promoter is present at the 5' end of RB1 gene. Hypermethylation of the CpG island within the RB1 promoter region has been described in unilateral retinoblastoma. In vitro and in vivo studies have suggested that methylation of the RB1 promoter dramatically reduces gene activity. In the present study methylation status of the CpG island within the promoter region of RB1 gene has been evaluated by methylation specific polymerase chain reaction to define the molecular mechanism responsible for retinoblastoma in Indian patients. One unilateral and two bilateral nonhereditary patients had methylation of the RB1 promoter region in which 6.6% of our patients had complete methylation of the RB1 promoter region. This study shows methylation of RB1 promoter is not a major mechanism for retinoblastoma patients in India. Methylation analysis is used in genetic counseling of the family.

Child, Preschool↗

PubMed2025

A functional assay to classify RB1 variants of uncertain significance.

PURPOSE: The RB1 gene encodes the retinoblastoma protein (pRB) playing a major role in cell cycle control, particularly by its interaction with E2F transcription factors. Familial forms of retinoblastoma are caused by germline pathogenic variants in the RB1 gene predisposing to retinoblastoma and other tumors. By analyzing the RB1 gene in patients with retinoblastoma, we found that missense variants often remain variants of uncertain significance (VUS). METHODS: To classify RB1 VUS, we developed a functional assay evaluating their impact on the ability of pRB to inhibit the activity of the E2F1 promoter, with a luciferase reporter gene. A set of 14 pathogenic/likely pathogenic and benign/likely benign RB1 variants was used for validation. RESULTS: We tested 16 VUS detected in patients with retinoblastoma and found that 9 VUS reduced the ability of pRB to inhibit E2F1 promoter. Among them, the (RB1) c.2263T>G p.(Phe755Val) variant showed a reduced level of pRB on Western blot, suggesting a defect in pRB stability. By applying the criterion PS3_moderate of the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification to this functional assay, 5 of the 9 VUS with functional impact could be classified as likely pathogenic. CONCLUSION: This functional assay can improve the molecular diagnosis of retinoblastoma predisposition by a better determination of pathogenic/likely pathogenic RB1 variants.

Humans↗

PubMed1998

Increased RB1 abnormalities in human primary prostate cancer following combined androgen blockade.

BACKGROUND: The RB1 proliferation control pathway is a critical determinant of cell cycle progression. Abnormalities of RB1 are found in a variety of cancers, and the association with human prostate cancer (CaP) was examined here. METHODS: RNA expression levels of RB1 in CaPs were examined by RT-PCR. RNA integrity was assessed by evaluating expression of an endogenous gene standard. RESULTS: Abnormally low RB1 mRNA expression was found in 12/33 (36%) of CaPs from patients who had received combined androgen blockade (CAB) treatment. In contrast, 6/48 (13%) untreated CaPs showed abnormally low expression. This difference was statistically significant (P = 0.015). In the samples from untreated patients, a higher frequency of abnormal RB1 was found in specimens with a higher Gleason grade (P = 0.038). In addition, one untreated stage C, grade 9 specimen was found to express RB1 transcripts lacking exon 22, as determined by sequencing of DNA from the truncated transcripts. CONCLUSIONS: These findings suggest that abnormalities of RB1 may contribute to hormone-withdrawal-related survival of CaP cells.

Androgen Antagonists↗

PubMed2005

Sensitive multistep clinical molecular screening of 180 unrelated individuals with retinoblastoma detects 36 novel mutations in the RB1 gene.

Retinoblastoma (RB) is a neoplasm of retinal origin caused by mutations in RB1, the retinoblastoma tumor suppressor gene. To facilitate genetics counseling and patient management, we adopted a multistep molecular screening assay for detecting RB1 mutations. This assay included DNA sequencing to identify mutations within coding exons and immediate flanking intronic regions, Southern blot analysis to characterize genomic rearrangements, and transcript analysis to characterize potential splicing mutations buried within introns. In a pilot investigation of 180 patients from North America, we identified germline RB1 mutations in 77 out of 85 bilateral RB patients (91%), 7 out of 10 familial unilateral (70%), and 6 out of 85 unilateral patients with no family history of RB (7%). Mutations included 36 novel alterations spanning the entire RB1 gene. Seven of these novel changes were missense or silent mutations. Sequence analysis predicted that, in five out of seven cases, the changes can cause aberrant splicing. This was confirmed by transcript analysis in four out of five cases. In addition, four intronic point mutations within nonconsensus sites activated cryptic splice sites. Without the transcript analysis, the significance of these 11 mutations would have remained undefined. In a separate investigation of a subset of unilateral RB tumors, we identified somatic biallelic RB1 gene inactivation in 34 out of 56 cases (61%) cases. In 14 tumors, only one of the two RB1 mutations could be detected, and in eight tumors, no mutations were detected. The absence of detectable RB1 mutations in eight bilateral cases and eight unilateral tumors suggests that alternative genetic mechanisms may underlie the development of RB in certain individuals.

DNA Mutational Analysis↗

PubMed2001

RB1 genetic testing as a clinical service: a follow-up study.

BACKGROUND: Genetic testing for inherited predisposition to diverse cancers has recently become available as a clinical service. We conducted a follow-up study of the initial series of US families who underwent RB1 genetic testing to evaluate long-term effects of the service. PROCEDURE: We enrolled 52 of 71 eligible families who responded to a follow-up study questionnaire administered 3-10 years after receipt of their RB1 results. Each family had one proband with unilateral, non-familial retinoblastoma, which is associated with a 12% pre-test probability of hereditary retinoblastoma. RB1 testing identified germline RB1 mutations in five patients, lowered the carrier probability to 2% in 21 patients, and did not substantially modify the carrier probability in the remaining 26. RESULTS: Diverse medical specialists offered and arranged for RB1 testing, and their recommendation was the most influential factor in the decision to be tested. Pre-test counseling was provided by ophthalmologists (30), oncologists (11), and geneticists and genetic counselors (11). Most respondents, regardless of test result, were satisfied and perceived gains from their genetic testing. Based on small numbers, families with reduced likelihood of hereditary retinoblastoma reported more positive outcomes. Parents of RB1 carriers were more likely to seek medical services, worry, and decide against having more children. CONCLUSIONS: This study demonstrates the feasibility of follow-up studies of families who had genetic testing. Results from our small series suggest that genetic information and counseling are important components of RB1 clinical genetic testing, and long-term adverse effects of testing are uncommon.

Adult↗

PubMed2005

Calcium-independent CaMKII activity is involved in ginsenoside Rb1-mediated neuronal recovery after hypoxic damage.

Recent studies have indicated that Ginsenoside Rb1, one of the major components of ginseng root, may play an important role in protecting cells from damage. Here, we investigated the neuroprotective activity of Rb1 after hypoxic injury in young rats. About 50% animals were dead by exposing hypoxic condition three times in three consecutive days. Then, the pretreatment with Rb1 prior to hypoxic stimulation reduced animal death to 12%, and also significantly reduced the recovery time from hypoxia-related, compromised symptoms in survived animals. Rb1 also significantly reduced levels of lactate dehydrogenase (LDH) release from primary hippocampal neurons which were maintained at low oxygen concentration, indicating increased neuronal survival by Rb1. Ca(2+)/calmodulin-dependent kinase II (CaMKII) activity in the hippocampal tissues of hypoxia-induced rats was decreased to about 50% of the control animal. Then Rb1-treatment prior to hypoxic stimulation significantly elevated Ca(2+)-independent kinase II activity when measured 48 hr after hypoxic stimulation. Thus, the present data suggest that calcium independent CaMKII activity may be involved in the process of ginsenoside Rb1-mediated recovery of neuronal cells after hypoxic damage.

Animals↗

PubMed1999

Inhibition by ginsenosides Rb1 and Rg1 of cocaine-induced hyperactivity, conditioned place preference, and postsynaptic dopamine receptor supersensitivity in mice.

A single or repeated administration of cocaine (15 mg/kg) in mice produced hyperactivity and conditioned place preference (CPP). Ginsenoside Rb1 (Rb1) and ginsenoside Rg1 (Rg1), prior to and during the cocaine treatment in mice, inhibited cocaine-induced hyperactivity and CPP. The development of enhanced postsynaptic dopamine (DA) receptor sensitivity in mice displaying a cocaine-induced CPP was evidenced by the enhanced response in ambulatory activity to the DA agonist, apomorphine (2 mg/kg). Rb1 and Rg1 inhibited the development of postsynaptic DA receptor supersensitivity. However, Rb1 and Rg1 did not show any antidopaminergic activity at the postsynaptic DA receptors, because the apomorphine-induced climbing behavior was not inhibited by Rb1 and Rg1. Therefore, it is presumed that Rb1 and Rg1 modulate DA activity induced by cocaine at the presynaptic DA receptors, and this modulation results in the inhibition of postsynaptic dopaminergic activation. These results suggest that the cocaine-induced CPP may be associated with enhanced DA receptor sensitivity. The inhibition by Rb1 and Rg1 of cocaine-induced hyperactivity and CPP may be closely related with the inhibition of dopaminergic activation induced by cocaine at the presynaptic DA receptors.

Animals↗

PubMed1997

p53 and Rb1 protein expression: are they prognostically useful in colorectal cancer?

The expression of the p53 and Rb1 proteins was examined in an unselected consecutive series of 250 primary operable colorectal carcinomas with a mean follow-up of 4.3 years (range 43-77 months). The overall cancer-specific mortality was 34.8%, with 87 cancer deaths and 35 deaths as the result of other causes. Expression of p53 protein was identified in 152 of 250 (60.8%) cases, with expression of Rb1 protein in 207 of 250 (82.8%) cases. There was no association of p53 or Rb protein expression with patient age, sex, tumour site, tumour size, tumour type, tumour grade, peritumoral fibrosis, tumour lymphocytic infiltrate, nature of the tumour margin, extramural vascular invasion, number of lymph nodes or high apical lymph node involved or local peritoneal infiltration by tumour, Dukes' stage or Jass group. There was no difference in overall survival or recurrence-free survival for those cases that showed p53 expression or Rb1 protein expression compared with those cases showing absence of p53 or Rb1 protein expression, although patients with tumours showing aberrant (reduced) Rb1 protein expression demonstrated shorter recurrence-free survival and overall survival. The effect of 'aberrant' Rb1 protein expression and shorter recurrence-free and overall survival did not, however, achieve independent statistical significance. The results from this study would suggest that expression of p53 and Rb1 proteins does not appear be useful in determining the prognosis of operable colorectal cancer.

Adult↗

PubMed2006

Oral absorption of ginsenoside Rb1 using in vitro and in vivo models.

This research attempts to clarify the cause for poor oral absorption of ginsenoside Rb1 (Rb1), one main ingredient of the well known Panax notoginseng saponins (PNS) for curing hemorrhage. Caco-2 cell monolayers were used as an in vitro model to reveal the transport mechanism of Rb1 across the intestinal mucosa. Moreover, the serum concentration-time profiles of Rb1 after tail venous (IV), portal venous (PV), intraduodenal (ID) and peroral (PO) administration to rats were compared to evaluate the first-pass effects of stomach, intestine and liver. In vitro experiments showed that uptake by Caco-2 cell monolayers was temperature dependent, but was not influenced by cyclosporine A and ketoconazole. The change in the apical pH showed no obvious effects on the uptake of Rb1. The uptake and transport were non-saturable, and flux from the apical compartment to the basolateral compartment (A-B) increased linearly with increasing concentration, which indicated a passive transport. Meanwhile, an apparent permeability coefficient of (5.90 +/- 1.02) x 10(-8) cm/s (C0 = 1 mg/mL) predicted an incomplete absorption. The investigation on the pharmacokinetic behavior of Rb1 after different routes of administration to rats showed a significant difference between PO (F(PO) was 0.64%), ID (F(ID) was 2.46%) and PV (F(PV) was 59.49%) administration, and the first-pass effect of the intestine is more significant than that of the stomach and liver in the absorption process. In summary, elimination in the stomach, large intestine and liver contributed to the poor absorption of Rb1, but the low membrane permeability might be a more important factor dominating the extent of absorption.

Administration, Oral↗

PubMed1997

The proliferation potential protein-related (P2P-R) gene with domains encoding heterogeneous nuclear ribonucleoprotein association and Rb1 binding shows repressed expression during terminal differentiation.

Terminal differentiation is associated with repression in the expression of the proliferation potential proteins (P2P) subset of heterogeneous nuclear ribonucleoprotein (hnRNP) proteins. We report here the cloning and characterization of a 5173-bp P2P-related (P2P-R) cDNA that contains a 4214-bp open reading frame. Probes to this cDNA detect a single 8-kb mRNA in multiple murine tissues and in proliferating 3T3T cells, but not in terminally differentiated 3T3T adipocytes. Evidence that this cDNA can encode peptides with domains for hnRNP association was established by showing that such peptides are recognized by two monoclonal antibodies known to detect core hnRNP proteins, and by showing that the C130 monoclonal antibody, produced against a cDNA-derived fusion protein, also selectively detects native P2P hnRNP proteins. In addition, P2P-R cDNA-derived fusion proteins bind single-stranded nucleic acids, and a P2P-R cDNA-derived antisense oligonucleotide selectively represses P2P expression. Because terminal differentiation is associated with modulation in Rb1 function, we assayed if products of this cDNA might interact with Rb1. Evidence that the P2P-R cDNA encodes a protein domain that binds Rb1 was established using a glutathione S-transferase fusion protein to selectively precipitate Rb1 from cellular extracts. Data also show that this binding is reduced by competition with the adenovirus E1a protein, indicating that binding occurs through the "pocket" domain of Rb1. These results establish that the P2P-R cDNA encodes protein domains involved in both hnRNP association and Rb1 binding and complement recent reports that localize Rb1 to sites of RNA processing in the nucleus.

Adipocytes↗

PubMed2005

Hepatoprotective effect of ginsenoside Rb1 and compound K on tert-butyl hydroperoxide-induced liver injury.

BACKGROUND/AIM: The main component of Panax ginseng, which have been reported by many researchers, are ginsenoside Rb1, Rb2 and Rc. Orally administered ginsenosides are metabolized to 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (compound K) by intestinal bacteria and absorbed to blood. To understand its hepatoprotective effect and its mechanism, the effects of ginsenoside Rb1 and its metabolite compound K on chemically injured HepG2 cells and mice were investigated. METHODS: Ginsenoside Rb1 and compound K were isolated from ginseng. Hepatotoxicity of HepG2 cells and mice was induced by tert-butyl hydroperoxide (t-BHP). Cytotoxicity for HepG2 cells and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) for mice as markers of hepatoprotective activity were measured. RESULTS: Compound K protected HepG2 cell cytotoxicity induced by t-BHP. However, ginsenoside Rb1 did not inhibit cytotoxicity. Nevertheless, both ginsenoside Rb1 and compound K significantly inhibited the increment of ALT and AST induced by t-BHP in mice, when it was orally administered. However, intraperitoneally administered ginsenoside Rb1 did not inhibit the increment of plasma ALT and AST induced by t-BHP in mice. These compounds did not exhibit antioxidant activity. However, compound K showed the potent membrane stabilizing activity more than ginsenoside Rb1. CONCLUSION: Compound K, which was produced from ginsenosides of Panax ginseng in intestine, could protect liver injury.

Animals↗

PubMed2004

Comprehensive screening for constitutional RB1 mutations by DHPLC and QMPSF.

Constitutional mutations of the RB1 gene are associated with a predisposition to retinoblastoma. It is essential to identify these mutations to provide appropriate genetic counseling in retinoblastoma patients, but this represents an extremely challenging task, as the vast majority of mutations are unique and spread over the entire coding sequence. Since 2001, we have implemented RB1 testing on a routine basis as part of the clinical management of retinoblastoma. As most screening techniques do not meet the requirements for efficient RB1 testing, we have devised a semi-automated denaturing high-performance liquid chromatography (DHPLC) method for point mutation detection combined with a quantitative multiplex PCR of short fluorescent fragments (QMPSF) approach to screen for gene rearrangements. We report the results of this comprehensive screening of all exons and promoter of RB1 in 192 unrelated patients, mostly of French origin. Among 102 bilateral and/or familial cases and 90 unilateral sporadic probands, mutations were identified in 83 (81.5%) and 5 (5.5%) cases, respectively. A total of 43 mutations have not been previously reported. The mutational spectrum was found to be significantly different from previous published series, displaying a surprising amount of splice mutations and large deletions. This study demonstrates the reliability of DHPLC for RB1 analysis, but also illustrates the need for a deletion scanning approach. Finally, considering the benefits to retinoblastoma patients, RB1 testing should be widely implemented in routine healthcare because our study clearly illustrates its feasibility.

Child, Preschool↗

PubMedDate not supplied

The nootropic properties of ginseng saponin Rb1 are linked to effects on anxiety.

Previous studies have shown that crude ginseng extracts enhance performance on shock-motivated tasks. Whether such performance enhancements are due to memory-enhancing (nootropic) properties of ginseng, or to other non-specific effects such as an influence on anxiety has not been determined. In the present study, we evaluated both the nootropic and anxiolytic effects of the ginseng saponin Rb1. In the first experiment, 80 five-day-old male chicks received intraperitoneal injections of 0, 0.25, 2.5 or 5.0 mg/kg Rb1. Performance on a visual discrimination task was evaluated 15 minutes, 24 and 72 hours later. Acquisition of a visual discrimination task was unaffected by drug treatment, but the number of errors was significantly reduced in the 0.25 mg/kg group during retention trials completed 24 and 72 hours after injection. Animals receiving higher dosages showed trends towards enhancement initially, but demonstrated impaired performance when tested 72 hours later. Rb1 had no effect on response rates or body weight. In the second experiment, 64 five-day-old male chicks received similar injections of Rb1 (0, 0.25, 2.5 or 5.0 mg/kg) and separation distress was evaluated 15 minutes, 24 and 72 hours later. Rb1 produced a change in separation distress that depended on the dose and environmental condition under which distress was recorded. These data suggest that Rb1 can improve memory for a visual discrimination task and that the nootropic effect may be related to changes in anxiety.

Animals↗

PubMed2004

A one-step immunochromatographic assay for detecting ginsenosides Rb1 and Rg1.

An immunochromatographic strip test has been developed for detecting ginsenosides Rb1 (G-Rb1) and Rg1 (G-Rg1). This qualitative assay system is useful as a rapid screening method for detecting G-Rb1 and G-Rg1 in plants and plant preparations. Our assay is a competitive immunoassay that uses anti-G-Rb1 and anti-G-Rg1 monoclonal antibodies (MAbs) and a detection reagent that contains colloidal gold particles coated with anti-G-Rb1 and anti-G-Rg1 MAbs. Detection limits are 2 microg mL(-1) for both G-Rb1 and G-Rg1.

Animals↗

PubMed2006

Unilateral retinoblastoma, lack of familial history and older age does not exclude germline RB1 gene mutation.

Conclusive identification of RB1 mutations in retinoblastoma is predicted to improve the clinical management of affected children and relatives. However, despite clear clinical benefits, RB1 screening remains difficult, most of the alterations being unique and randomly distributed throughout the entire coding sequence. In this report, we present the results of a constitutional RB1 analysis undertaken in our institution over the last four years. The detection of RB1 gene deletion or mutation was performed by Southern blot and sequence analyses in 73 patients (including three families with 2, 3 and 3 probands, respectively). Complementary constitutional chromosome and fluorescent in situ hybridization (FISH) analyses of RB1 gene were applied in cases where hereditary retinoblastoma was suspected despite negative detection. Altogether, germline abnormalities were found in 11% (4/36 patients) of sporadic unilateral retinoblastoma (median age, 21.5 months) and 86% (32/37 patients) of sporadic bilateral or positive familial history retinoblastoma (median age, 5 months). The spectrum of germline alterations found in 31 distinct families included 12 nonsense mutations (39%); 10 point insertions or deletions with frameshift (32%); 4 mutations and 1 deletion affecting splice sites (16%); 2 missense mutations (6%); and 2 large deletions (6%). A total of 15 mutations have not been previously reported. In this small series, splicing mutations were associated with bilateral disease whilst most of the frameshift mutations were identified in patients with an early age at diagnosis, bilateral disease or hereditary forms of the disease. This study confirms that screening for constitutional RB1 mutation should become an integral part of current management of any patient affected by retinoblastoma irrespective of the tumour laterality and familial background.

Adult↗

PubMed2006

The antistress effect of ginseng total saponin and ginsenoside Rg3 and Rb1 evaluated by brain polyamine level under immobilization stress.

The present study aims to demonstrate the ability of ginseng total saponin (GTS), ginsenosides Rg3 and Rb1 to reduce brain polyamine levels in immobilization-stressed gerbil mice. A previous study reported that ginsenosides had an anti-stress property. So, we tested the anti-stress effect of ginseng by investigating the brain level of polyamine, a well-known stress stimuli marker. We determined the brain polyamine levels under 30-min immobilization stress in pretreating GTS (100 mgkg(-1), oral), ginsenosides Rg3 and Rb1 (10 mgkg(-1), oral, respectively). Then, we compared polyamine levels between the non-stressed mouse and the stressed mouse which had taken saline orally to check the placebo effect. Putrescine (PUT) levels were significantly increased (P < 0.01) in the stressed condition, but it was reduced in pretreatment of GTS, ginsenosides Rg3 (P < 0.01, respectively) and Rb1 (P < 0.001) under 30-min immobilization stressed-mouse. However, other polyamine levels did not change regardless of stressed condition or GTS-, ginsenosides Rg3- and Rb1-treated stressed condition. These results mean that only PUT could be a marker for stress and GTS, ginsenosides Rg3 and Rb1 administration lead to an anti-stress effect. Thus, our studies indicate that GTS, ginsenosides Rg3 and Rb1 may play a neuroprotective role in the immobilization-stressed brain.

Acetyltransferases↗

PubMed2002

Preferential expression of RB1-inducible coiled-coil 1 in terminal differentiated musculoskeletal cells.

RB1-inducible coiled-coil 1 (RB1CC1) is a nuclear DNA-binding protein that can induce RB1 (retinoblastoma 1) expression. RB1CC1 is abundantly expressed in human musculoskeletal and cultured osteosarcoma cells. The present study analyzed the expression of RB1CC1 and RB1 in osteosarcoma cells and in musculoskeletal cells of human embryos to evaluate the contribution of both genes to the maturational process of musculoskeletal cells. The amount of RB1CC1 message was closely related to RB1 expression in various osteosarcoma cell lines. RB1CC1 expression was difficult to detect in immature proliferating chondroblasts or myogenic cells in human embryos, but became obvious and prominent concomitantly with the maturation of osteocytes, chondrocytes, and skeletal muscle cells. RB1CC1 expression in these musculoskeletal cells increased with RB1 expression, which is linked to the terminal differentiation of many tissues and cells. In addition, the introduction of wild-type RB1CC1 decreased the formation of macroscopic colonies in the cell growth assay. Accordingly, both RB1CC1 and RB1 genes preferentially co-expressed and contributed to the maturation of human embryonic musculoskeletal cells, and may regulate the proliferative activity and maturation of tumor cells derived from these tissues.

Autophagy-Related Proteins↗