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PubMed2006

[The protective effects of ginsenoside RG1 and Rb1 against damage of HaCaT cells by ultraviolet B].

AIM: To investigate the survival rate and the level of HaCaT cells damage with ultraviolet B (UVB) radiation at various doses, and observe the protective effects of ginsenoside Rg1 and Rb1 in vitro. METHODS: MTT assay was employed to analyze the cell survival rate after UVB radiation of 30, 60, 90 and 120 mJ x cm(-2). The damage of nucleolus and the protective effects of ginsenoside Rg1 and Rb1 were scanned by Hoechst 33258 staining and single cell gel electrophoresis assay (SCGE). RESULTS: It was found that the cell survival rate decreased gradually and the damage of nucleolus aggravated as the radiation dose increased from 30 mJ x cm(-2) to 120 mJ x cm(-2). At the dose of 20 microg x mL(1-), obvious protective effect of ginsenoside Rg1 and Rb1 can be observed against UVB radiation-induced HaCaT cells growth inhibition and nucleolus damage. CONCLUSION: UVB radiation inhibits HaCaT human keratinocytes growth and ginsenoside Rg1 and Rb1 can relief the damage.

Apoptosis↗

PubMed1990

Inhibitory effects of ginsenoside Rg1 and Rb1 on rat brain microsomal Na+,K(+)-ATPase activity.

Rat brain microsomal Na+, K(+)-ATPase activity was inhibited significantly and rapidly by ginsenoside Rb1. The IC50 of Rb1 for Na+,K(+)-ATPase was 6.3 +/- 1.0 mumol/L. The inhibition was enhanced with increasing the concentration of Rb1 or decreasing that of Na+ and K+. Kinetic analysis revealed that ginsenoside was an uncompetitive inhibitor with respect to ATP. The inhibitory effect of Rg1 on rat brain microsomal Na+,K(+)-ATPase was much weaker than that of Rb1.

Animals↗

PubMed1989

[Effect of ginsenosides Rb1 and Rg1 on lipid peroxidation of rat in vitro].

Ginsenosides Rb1 and Rg1 were found to inhibit to some degree both VitC-NADPH and Fe2(+)-cysteine induced lipid peroxidation of rat liver and brain microsomes. However, the inhibitory effect of Rb1 and Rg1 was obvious in liver microsomes, especially in Vit C-NADPH induced lipid peroxidation of liver microsomes. Besides, Rb1 was shown to be more potent than Rg1 in inhibiting VitC-NADPH or Fe2(+)-cysteine induced lipid peroxidation. The inhibitory effect of Rb1 on VitC-NADPH induced lipid peroxidation was similar to that of VitE at the same concentration.

Animals↗

PubMed1989

[Effects of Panax notoginseng saponin Rb1 and Rg1 on myocardial action potential and slow inward current].

The effects of Rb1, Rg1 (purified saponin of Panax notoginseng) on contraction force, action potential and slow inward current of guinea pig papillary muscles were studied by intracellular microelectrodes and voltage clamp techniques. The contraction force was decreased and the APD20 was shortened in the presence of Rb1 1 mg/ml, while the RP, APA and Vmax remained unchanged. The amplitude of Isi was decreased from a peak value of 9.8 +/- 1.6 to 7.3 +/- 3.4 microA after 20 min perfusion with Rb1 solution. This effect was reversed by increasing calcium concentration. Rg1 1 mg/ml decreased the contraction force significantly without affecting the configuration of action potential and the amplitude of slow inward current. The results indicate that Rb1 has a blocking effect on calcium channels, but Rg1 has not.

Action Potentials↗

PubMed1994

[Study on the nootropic mechanism of ginsenoside Rb1 and Rg1--influence on mouse brain development].

Weaning mice were supplied drinking water containing Rb1 or Rg1 0.125 or 0.25 mg.ml-1 for 4 weeks. Rb1 (28.6 and 56.1 mg.kg-1) and Rg1 (27.4 and 53.9 mg.kg-1) were found to accelerate young mice body and brain development as well as facilitate memory acquisition in step down and step through avoidance response tests. With the technique of quantitative measurement synapses, we found for the first time that Rb1 and Rg1 administration for 4 weeks can increase synapse number in the hippocampal CA3 region of mice. This is the morphological basis for explaining Rb1 and Rg1 induced facilitation of learning and memory.

Animals↗

PubMed1994

Characterization of the human RB1 promoter and of elements involved in transcriptional regulation.

The retinoblastoma gene (RB1) is a recessive oncogene implicated in a number of human tumors. Although the RB1 gene is expressed in most proliferating cells, there is considerable evidence for the transcriptional regulation of this gene. Therefore, we have performed a detailed analysis of the regulatory elements in the promoter of the human RB1 gene. Deletion analysis of the 5' upstream region determined the location of the basal promoter to be between -208 and -179 nucleotides relative to the translational start. This region contains essential binding sites for the transcription elements ATF and SP1 and potentially important sites for E2F and steroid hormone responsiveness but no TATA or CAAT boxes. Primer extension and RNase protection analysis identified two initiation sites at -176 and -128 base pairs, both downstream of the promoter. Cotransfection experiments revealed repression of the RB1 promoter by its protein product p110RB1. This repression has been mapped to the core promoter region containing the E2F-binding site; however, this site is not required for autorepression.

Activating Transcription Factors↗

PubMed1993

Molecular cloning and characterization of the mouse RB1 promoter.

We report the isolation and characterization of the mouse RB1 promoter and surrounding DNA sequences, and the identification of elements required for basal transcriptional activity. The mouse RB1 promoter, like the human homologue, has a high G + C content, constitutes a CpG island and is devoid of typical TATA and CAAT boxes. The first 235 base-pairs upstream of the translation initiation codon in the mouse promoter exhibit 80% sequence homology with the human sequence. This homology includes a region which contains putative binding sites for the transcription factors Sp1, ATF and E2F/DRTF1. Four major transcription initiation sites were identified downstream of this conserved region. Mutational analysis revealed that the Sp1 and ATF binding sites, but not the putative E2F/DRTF1 binding site, are critical for promoter activity. Complete disruption of the putative Sp1 and ATF sites abrogated transcription, whereas the introduction of point mutations, previously identified in the Sp1 and ATF sites in two low penetrance retinoblastoma families, reduced promoter activity in a cell type specific manner. Less reduction in activity occurred in retinoic acid induced differentiated P19 cells and NIH3T3 mouse fibroblasts than in undifferentiated embryonal carcinoma P19 cells. Activity of the RB1 promoter was found to be stimulated in retinoic-acid induced differentiated P19 cells compared to undifferentiated P19; this stimulation required intact Sp1 and ATF sites but not the putative E2F/DRTF1 binding site. Our results indicate that basal level of RB1 expression is governed by Sp1 and ATF.

Animals↗

PubMed1996

The spectrum of RB1 germ-line mutations in hereditary retinoblastoma.

We have searched for germ-line RB1 mutations in 119 patients with hereditary retinoblastoma. Previous investigations by Southern blot hybridization and PCR fragment-length analysis had revealed mutations in 48 patients. Here we report on the analysis of the remaining 71 patients. By applying heteroduplex analysis, nonisotopic SSCP, and direct sequencing, we detected germ-line mutations resulting in premature termination codons or disruption of splice signals in 51 (72%) of the 71 patients. Four patients also showed rare sequence variants. No region of the RB1 gene was preferentially involved in single base substitutions. Recurrent transitions were observed at most of the 14 codons within the RB1. No mutation was observed in exons 25-27, although this region contains two CGA codons. This suggests that mutations within the 3'-terminal region of the RB1 gene may not be oncogenic. When these data were combined with the results of our previous investigations, mutations were identified in a total of 99 (83%) of 119 patients. The spectrum comprises 15% large deletions, 26% small length alterations, and 42 % base substitutions. No correlation between the location of frameshift or nonsense mutations and phenotypic features, including age at diagnosis, the number of tumor foci, and manifestation of nonocular tumors was observed.

Adolescent↗

PubMed1997

Rb1 gene expression in B-cell lymphocytic leukaemia cases with deletion in the 13q14 region.

Recent studies have been carried out to delineate further the role of the Rb1 gene in B-cell chronic lymphocytic leukaemia (B-CLL). The suggested role of the Rb1 gene in this disease was based on cytogenetic data. CLL patients (40 in toto) were examined using cytogenetic and molecular biological methods. R-banding analysis of metaphase chromosomes revealed aberrations in only seven cases containing either the Rb1 gene or a chromosome 13 monosomy. No evident differences were found by RT-PCR analysis of Rb1 gene expression. The amounts of the RT-PCR products obtained appeared to be approximately equal in all cases, and was independent of the clinical stage, immunophenotypes and LPS or TPA stimulation.

Cells, Cultured↗

PubMed2004

Two independent RB1-inactivating mutations in peripheral blood DNA of a hereditary retinoblastoma patient.

We report the presence of a hemizygous inactivating germ-line RB1 mutation (a recurrent g.78250C-->T transition, resulting in a stop codon in exon 17) in peripheral blood DNA from a patient with hereditary bilateral retinoblastoma. Hemizygosity was established by sequencing that showed no traces of the wild-type C nucleotide and by quantitative real-time PCR, which showed loss of one copy of exon 17. Genotyping of the RB1 locus with several polymorphic markers delineated a maximal deletion region between g.76875 and g.99426, including exons 15-17 and a large piece (21 kb) of intron 17. The heterozygosity for the mutation found in skin fibroblasts proves that the intragenic RB1 deletion probably took place in the definitive hematopoietic lineage of the patient. The presence of a null Rb-/- genotype in the hematopoietic cell lineage suggests that the white blood cells of the proband could be useful in the investigation of the role of complementary RBI family proteins in the control of the cell cycle.

Blood Cells↗

PubMed1992

No alterations in exon 21 of the RB1 gene in sarcomas and carcinomas of the breast, colon, and lung.

Studies of mutant genotypes of the retinoblastoma susceptibility gene (RB1) in different solid tumors have mainly been concentrated on the demonstration of loss of heterozygosity (LOH) at both internal and external polymorphic sites. One reason for this is the complex organization of the gene. The p105RB protein has been shown to interact with both DNA and regulatory cellular proteins and oncoproteins. The amino acids encoded by exon 21 are implicated in several of these interactions. Both point mutations and intragenic deletions involving exon 21 have previously been reported in human tumors. We have examined RB1 exon 21 from a number of human tumor types where significant LOH in or around the RB1 gene has been reported. DNA from 78 primary tumors was amplified using the polymerase chain reaction (PCR) with primers covering exon 21, followed by constant denaturant gel electrophoresis (CDGE). The 78 tumors included 11 breast carcinomas, 30 nonsmall cell lung carcinomas, 6 colon carcinomas, and 31 sarcomas. The small cell lung cancer cell line NCI-H209, previously shown to harbour a point mutation in codon 706: TGT- greater than TTT (Cys- greater than Phe), was detected using CDGE. Apart from this control mutant cell line, we did not detect any mutations in the examined region in any of the tumors.

Base Sequence↗

PubMed2003

Mutational screening of the RB1 gene in Indian patients with retinoblastoma reveals eight novel and several recurrent mutations.

Retinoblastoma is the most common primary intraocular malignancy in children, caused by inactivation of the RB1 gene on chromosome 13. We carried out a mutational screen of the exons and promoter of the RB1 gene in Indian patients with retinoblastoma in order to determine the range of mutations giving rise to disease. Forty-seven patients were screened for mutations in all exons and promoter of the RB1 gene by single strand conformation polymorphism followed by sequencing. Tumors were available from 27 patients (12 bilateral and 15 unilateral retinoblastoma) while only peripheral blood was available from 20 patients, all with bilateral disease. Mutations were found in 22 patients, 9 from the analysis of tumors and 13 from peripheral blood. Eight novel mutations were identified, including 4 single base changes, 2 small deletions and 1 duplication. These are g.64365T>G (Tyr325Ter), g.78131G>A (Trp515Ter), g.150061G>T (Glu587Ter), g.170383C>G (S834X), g.41924A>C (IVS3-2A>C), g.150064ins4, g.160792del22, and g.76940del14 (IVS15 del +20-33). Almost all mutations produced nonsense codons or frameshifts. Recurrent mutations, especially at CpG sites were seen predominantly. Detectable mutations in exons were found in 46% of patients tested. Large deletions, epigenetic changes as well as mutations in non-coding regions may be the cause of disease in the remainder of patients. Knowledge of the full range of mutations can aid in the design of screening tests for individuals at risk.

Child↗

PubMed2005

Identification of 26 new constitutional RB1 gene mutations in Spanish, Colombian, and Cuban retinoblastoma patients.

Constitutional mutations in the RB1 gene predispose to retinoblastoma development. Hence genetic screening of retinoblastoma patients and relatives is important for genetic counseling purposes. In addition, RB1 gene mutation studies may help decipher the molecular mechanisms leading to tumors with different degrees of penetrance or expressivity. In the course of genetically screening of 107 hereditary and non-hereditary retinoblastoma patients (11 familiar bilateral, 4 familiar unilateral, 49 sporadic bilateral and 43 sporadic unilateral) and kindred from Spain, Colombia and Cuba, using direct PCR sequencing, we observed 45 distinct mutations and four RB1 deletions in 53 patients (9 familiar bilateral, 2 familiar unilateral, 31 sporadic bilateral and 11 sporadic unilateral). Most of these mutations (26/45, 57%) have not been reported before. In 32 patients, the predisposing mutations correspond to nonsense (mainly CpG transitions) and small insertions or deletions whose expected outcome is a truncated Rb protein that lacks the functional pockets and tail. Five single aminoacid replacements and seventeen mutations affecting splicing sites were also observed in retinoblastoma patients. Two of these sixteen mutations are of unclear pathogenic nature.

Colombia↗

PubMed1995

A yeast artificial chromosome contig that spans the RB1-D13S31 interval on human chromosome 13 and encompasses the frequently deleted region in B-cell chronic lymphocytic leukemia.

Abnormalities involving chromosome 13 have been reported as the only cytogenetic change in B-cell chronic lymphocytic leukemia (BCLL). Deletions are the most common cytogenetic abnormality and always involve 13q14, but when translocations are seen, the consistent breakpoint is always in 13q14. It is now established that deletions, distal to the RB1 gene in 13q14, are invariably associated with these translocations. We have recently described the smallest such deletion from a series of rearrangements from these tumors isolated in somatic cell hybrids, which spans approximately 1 Mb. In this report, we present the results of a series of a chromosome walking experiments using YACs and have been able to span this small deletion, which must contain the gene that is frequently deleted in BCLL. Four probes from 13q14 (RB1-mgg15-D13S25-D13S31) were used to isolate corresponding YACs for each of the markers. The chromosomal location of these YACs was verified using FISH, which also demonstrated their nonchimeric nature. Vectorette end rescue was then used to demonstrate the overlap of the YACs and to isolate new clones to complete the contig. The extremes of the contig were shown to cross the chromosome 13 translocation breakpoints isolated in somatic cell hybrids that carry the derivatives of chromosome 13 involved in the smallest BCLL deletion. This YAC contig covers the entire deletion and will prove a valuable resource to begin isolating genes from this region. In addition, we have isolated YACs corresponding to the RB1 locus, which extends the contig over a 3.8-cM distance on the chromosome.

Base Sequence↗

PubMed1991

No evidence for sequences structurally related to the RB1 gene in the human genome.

The retinoblastoma (RB1) gene is a ubiquitously expressed gene encoding a cell-cycle control protein. Inactivation of this gene plays a crucial role in the development of retinoblastoma, osteosarcoma, and other tumors. In a search for structurally related gene sequences we identified a 5.5-kb BamHI fragment strongly cross-hybridizing with the 5' end of the RB1 cDNA. Molecular cloning, in situ hybridization, restriction mapping, and sequence analysis identified this DNA segment as the 28S rRNA gene. The absence of other cross-hybridizing sequences suggests that the RB1 gene is not part of a structurally related gene family.

Base Sequence↗

PubMed1996

Mapping the homolog of the human Rb1 gene to chromosome 14 of higher primates.

The Rb1 gene has been implicated with retinoblastoma and is located on human Chromosome (Chr) 13q14.2. A unique sequence human Rb1 cosmid DNA probe has been used to localize this region on apes' Chr 14 by the FISH technique. The conservation of the Rb1 gene in higher primates at the corresponding equivalent chromosome locus (14q14) of the human may serve as a phylogenetic marker to further trace the evolutionary pathway of human descent.

Animals↗

PubMed2003

Ginsenosides Rb1 and Rg1 effects on survival and neurite growth of MPP+-affected mesencephalic dopaminergic cells.

Ginsenosides Rb1 and Rg1 are the main active ingredients of Panax ginseng C.A. Meyer (Araliaceae). They appear to exert protection against ischaemia and anoxic damage in animal models, suggesting an antioxidative and cytoprotective role. In our study, primary cultures from embryonic mouse mesencephalon are applied to examine the effects of these two ginsenosides on neuritic growth of dopaminergic cells and their survival affected by 1-methyl-4-phenylpyridinium-iodide (MPP(+)). Ginsenoside Rb1 (at 10 microM) enhanced the survival of dopaminergic neurons by 19% compared to untreated control. MPP(+) (at 1 microM) significantly reduced the number of dopaminergic neurons and severely affected neuronal processes. Both ginsenosides counteracted these degenerations and significantly protected lengths and numbers of neurites of TH(+) cells. Both compounds however could not prevent the cell loss caused by MPP(+). Our study thus indicates partial neurotrophic and neuroprotective actions of ginsenosides Rb1 and Rg1 in dopaminergic cell culture.

1-Methyl-4-phenylpyridinium↗

PubMed2004

Detection of allelic imbalance in the gene expression of hMSH2 or RB1 in lymphocytes from pedigrees of hereditary, nonpolyposis, colorectal cancer and retinoblastoma by an RNA difference plot.

A number of phenotypes in hereditary disorders or common diseases are associated with specific genotypes. However, little is known about the molecular basis of phenotypic variation among individuals carrying the same mutation or polymorphism. Here, a highly quantitative approach was taken to examine a relative amount of mRNA from two polymorphic alleles with a coefficient of variation of less than 10% using an RNA difference plot (RDP). RDP analysis revealed that most genes examined were expressed in equal amount from the two alleles in normal lymphocytes. In contrast, the relative amounts of hMSH2 or RB1 mRNAs carrying premature termination codons were significantly reduced compared with those of wild-type mRNAs in lymphocytes from carriers of hereditary, nonpolyposis, colorectal cancer and hereditary retinoblastoma. The balance of allelic expression of the RB1 was also significantly impaired in a pedigree of retinoblastoma carrying a missense mutation in codon 661. The relative expression of the mutant to the wild-type RB1 alleles among the carriers varied from 0.40 to 2.39. The analysis of the expression diversity of a disease-associated allele by RDP could provide a novel approach to elucidating the mechanisms underlying phenotypic variation among individuals carrying an identical mutation or polymorphism at a single locus.

Alleles↗