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At least 73 records · Page 4Linked to original sources
PubMed1988

Structures of the anticancer compounds N-(2-hydroxyethyl)-2-(3-nitro-1,2,4-triazol-1-yl)-acetamide (RB-6110) and 5-(1-aziridinyl)-3-nitro-1-(3-oxo-1-butyl)-1,2,4- triazole (RB-6162).

RB-6110: C6H9N5O4, Mr = 215.17, monoclinic, C2/c, a = 20.595 (3), b = 4.713 (1), c = 19.914 (4) A, beta = 110.69 (1) degree, V = 1808.3 A3, Z = 8, Dx = 1.588 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.838 mm-1, F(000) = 675, T = 298 K, final R = 0.042 for 1219 observed reflections with I greater than or equal to 1.5 sigma (I). RB-6162: C8H11N5O3, Mr = 225.21, monoclinic, P2(1)/c, a = 7.515 (1), b = 14.758 (2), c = 9.813 (1) A, beta = 108.49 (1) degree, V = 1032.1 A3, Z = 4, Dx = 1.450 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.927 mm-1, F(000) = 472, T = 298 K, final R = 0.042 for 1113 observed reflections with I greater than or equal to 1.5 sigma (I). RB-6110 and RB-6162 are 3-nitro-1,2,4-triazoles with potential application as anticancer agents. The nitro groups are in the plane of the aromatic triazole ring with dihedral angles of 1.2 (4) and 4.6 (4) degrees, respectively. The arizidine substituent of RB-6162 is almost perpendicular [dihedral angle 80.1 (4) degrees] to the triazole plane. Molecular-orbital calculations on RB-6162 have confirmed that this geometry is energetically favoured. The energy barrier to rotation about the triazole-aziridine bond has been determined as 51.5 (5) kJ mol-1 by the dynamic NMR method.

Antineoplastic Agents↗
PubMed1996

Inactivation of retinoblastoma gene product RB or an RB-related protein by SV40 T antigen in MDCK epithelial cells results in massive apoptosis.

SV40 T antigen (LT) transformation of renal MDCK epithelial cells resulted in massive apoptosis in the presence of serum. Cell death was dependent on the ability of LT to bind RB or a related protein, since MDCK cells expressing LT mutants unable to bind RB did not die. Apoptosis could be rescued by treatment of cells with EGF and TPA, a property linked to their ability to promote cell growth. Our results indicate an inverse correlation between proliferation and apoptosis. Thus LT transformation induced survival-factor dependence in epithelial cells, in contrast to its effect in fibroblasts. RB inactivation also resulted in a strong down-regulation of c-myc and c-fos, which were previously found to be highly and constitutively expressed in epithelial cells. RB gene transfer in MDCK(LT) cells restored cell viability and high c-myc expression. C-myc gene transfer in these cells also resulted in a significant survival effect. These results suggest that RB anti-cell death activity is at least partly mediated by up-regulation of c-myc. Overexpression of Bcl2 also protected cells against apoptosis. The role of RB and c-myc in cell survival is discussed and related to maintenance of the differentiation state rather than to their properties in cell cycle progression.

Journal Article↗
PubMed1987

Functional properties of Salmonella minnesota Rb-bound and Rb-unbound cell fractions in elderly donors.

The capacity of Salmonella minnesota R345 (Rb) binding to human peripheral blood lymphocytes allows the recovery of Rb-bound and Rb-unbound cell populations that elicit different functions. Here, we have applied this method to lymphocytes from aged individuals to evaluate the possibility that such an approach could reverse the senescence-related impaired immune responsiveness. In this regard we show that Rb binding augments either spontaneous or T-dependent plaque-forming cell generation in Rb-unbound fraction. By contrast, Rb-bound cells are enriched for lymphocytes releasing several lymphokines. This experimental approach seems to represent a useful tool to elucidate better the age-related alterations of the immune function.

Aged↗
PubMed2000

Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF.

We present evidence that Rb forms a repressor containing histone deacetylase (HDAC) and the hSWI/SNF nucleosome remodeling complex, which inhibits transcription of genes for cyclins E and A and arrests cells in the G1 phase of the cell cycle. Phosphorylation of Rb by cyclin D/cdk4 disrupts association with HDAC, relieving repression of the cyclin E gene and G1 arrest. However, the Rb-hSWI/SNF complex persists and is sufficient to maintain repression of the cyclin A and cdc2 genes, inhibiting exit from S phase. HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF then appear to maintain the order of cyclin E and A expression during the cell cycle, which in turn regulates exit from G1 and from S phase, respectively.

Binding Sites↗
PubMed2003

Synthesis of group 1 metal 2,6-diphenylphenoxide complexes [M(OC6H3Ph2-2,6)] (M = Li, Na, K, Rb, Cs) and structures of the solvent-free complexes [Rb(OC6H3Ph2-2,6)]x and [Cs(OC6H3Ph2-2,6)x: one-dimensional extended arrays of metal aryloxides.

Reaction of 2,6-diphenylphenol (HOC(6)H(3)Ph(2)-2,6) with (n)BuLi, NaH, KH, or Rb or Cs metal in benzene gives the solvent-free complexes [M(OAr)]x in excellent yield. The complex [Rb(OC(6)H(3)Ph(2)-2,6)](x)() exhibits a ladderlike structure in the solid state with triply bridging oxygen atoms and Rb-O distances of 2.743(3), 2.930(2), and 2.973(2) A. The Rb cations interact with the pi-electron cloud of the arene moieties, giving rise to a high Rb coordination number. The cesium-containing congener forms a layered, columnlike structure consisting of [Cs(2)(mu(2)-OAr)(2)] units, with nearly identical Cs-O distances of 2.945(2) and 2.947(2) A. The individual layers are held together solely by Cs-arene pi-interactions.

Journal Article↗
PubMed1993

Sp-1 binds promoter elements regulated by the RB protein and Sp-1-mediated transcription is stimulated by RB coexpression.

The retinoblastoma (RB) protein is implicated in transcriptional regulation of at least five cellular genes, including c-fos, c-myc, and transforming growth factor beta 1. Cotransfection of RB and truncated promoter constructs has defined a discrete element (retinoblastoma control element; RCE) within the promoters of each of these genes as being necessary for RB-mediated transcription control. Previously, we have shown that RCEs form protein-DNA complexes in vitro with three heretofore unidentified nuclear proteins and mutation of their DNA-binding site within the c-fos RCE results in an abrogation of RCE-dependent transcription in vivo. Here, we demonstrate that one of the nuclear proteins that binds the c-fos, c-myc, and transforming growth factor beta 1 RCEs in vitro is Sp-1 and that Sp-1 stimulates RCE-dependent transcription in vivo. Moreover, we show that Sp-1-mediated transcription is stimulated by the transient coexpression of RB protein. We conclude from these observations that RB may regulate transcription in part by virtue of its ability to functionally interact with Sp-1.

3T3 Cells↗
PubMed2003

Binding of 1 Rb+ accelerates dephosphorylation of the Na+,K+-ATPase without leading to Rb+ occlusion.

In steady-state conditions and for concentrations of the K(+)-congener Rb(+) less than 2.5 mM, Rb(+)-dependent ATPase activity is significantly higher than the steady-state rate of breakdown of Rb(+)-occluded states, a discrepancy that disappears at sufficiently high [Rb(+)]. Direct experimental evidence is provided that supports the explanation that the binding of a single Rb(+) to the phosphoenzyme conformer E(2)P accelerates dephosphorylation without leading to the occlusion of the cation.

Animals↗
PubMed1998

[Study on the status of methylation of Rb gene promoter in human esophageal cancer and effect of NMBzA on Rb gene promoter in monkey esophageal epithelium].

OBJECTIVE: To elucidate the cause of abnormal Rb expression in esophageal cancer (EC). METHODS: Methylation of Rb gene promoter was examined with restriction endonuclease digestion and PCR amplification. RESULTS: Of the 30 specimens of EC, 10 (33.3%) had Msp I type hypermethylation of the Rb gene promoter while 12 (40.0%) had Hpa II type hypermethylation and one had both type of hypermethylation. In monkey fed with a single dose of NMBzA (30 mg/kg) on day 0, increasing hypermethylation of both types of the Rb gene promoter in esophageal epithelium was found on day 1, 2 and 3 but reduced on day 5. CONCLUSION: These data suggest that abnoromal expression of Rb gene may be related to hypermethylation of its promoter and carcinogen NMBzA can induce such hypermethylation in monkey esophageal epithelium.

Animals↗
PubMedDate not supplied

Expression of the RB protein, allelic imbalance of the RB gene and amplification of the CDK4 gene in metaplasias, dysplasias and carcinomas in Barrett's oesophagus.

In the present study, the role of allelic loss at the retinoblastoma gene (RB), expression of the retinoblastoma protein (pRb) and amplification at the CDK4 gene in the metaplasia--dysplasia--carcinoma sequence in Barrett's oesophagus (BO) was investigated. Samples of metaplastic specialised epithelium (SE; n = 28), low-grade dysplasia (LGD; n = 21), high-grade dysplasia (HGD; n = 19) and invasive adenocarcinoma (CA; n = 35) derived from 36 oesophagectomy specimens were included. Of the cases that were informative for the RB gene (n = 27), loss of heterozygosity (LOH) was found in none of the 22 SE, in none of the 14 LGD, in 1 of the 12 HGD (8.3%) and in 5 of the 27 CA (18.5%). Immunohistochemically, an enhanced expression of pRb protein in LGD, HGD and CA as compared with SE was found in most cases. In 4 carcinoma samples, however, a marked reduction (3 cases) or complete absence (1 case) of pRb protein expression was found. Two out of these 4 CA samples showed LOH in the RB gene whilst one case was heterozygous and one case was homozygous. In contrast to the positive controls used, CDK4 amplification was not detectable by means of differential PCR in any of the samples under investigation. The present study indicated that allelic loss of the RB gene occurs late in the metaplasia--dysplasia--carcinoma sequence in BO. Immunohistochemically determined loss of pRb protein expression may indicate LOH of the RB gene. CDK4 gene amplification does not seem to play a role in the development of oesophageal adenocarcinoma.

Adenocarcinoma↗
PubMed1990

Expression of the RB gene under the control of MuLV-LTR suppresses tumorigenicity of WERI-Rb-27 retinoblastoma cells in immunodefective mice.

Retinoblastomas arise by the loss of the retinoblastoma (RB) gene. The isolation of the RB gene and its expression in RB protein defective tumor cells permits direct tests of the ability of the protein to act as a tumor suppressor. We demonstrate that a functional RB gene introduced into WERI-Rb-27 retinoblastoma cells by retrovirally mediated gene transfer can suppress their tumorigenicity in immunodefective mice.

Animals↗
PubMed1982

Radiation absorbed dose estimates for positron emission tomography (PET): K-38, Rb-81, Rb-82, and Cs-130.

Radiation absorbed dose estimates were made for K-38, Rb-81, Rb-82, and Cs-130, potential radionuclides for myocardial and brain studies with positron emission tomography (PET). Biodistribution data for K-42, Rb-86, and Cs-137 in rats were used, together with the most recent radiation absorbed dose computational techniques and data. Renal radiation absorbed doses for K-38, Rb-81, Rb-82, and Cs-130 were estimated to be 56, 120, 19, and 150 mrad, respectively, per mCi administered. Corresponding radiation absorbed doses in the heart were 42, 54, 13, and 68 mrad/mCi. Radiation absorbed doses in the brain of 1.3, 3.5, 0.25, and 3.7 mrad/mCi were estimated for these four radionuclides.

Animals↗
PubMed2006

Subcellular localization, modification and protein complex formation of the cdk-inhibitor p16 in Rb-functional and Rb-inactivated tumor cells.

The cdk-inhibitor p16 is a tumor suppressor gene that is inactivated in many forms of cancer. Despite numerous studies, the exact mechanism of regulation of p16 has not been clarified, although the status of retinoblastoma (Rb) seems to be one important factor that influences the p16 expression. The specificity and validity of cytoplasmic localization of p16 observed in some tumors has further been questioned. Here, by subcellular fractionation of Rb-functional and Rb-inactivated cell lines, we show that p16 indeed is expressed in the cytoplasm as well as in the nucleus. Post translational modifications of p16 in different subcellular compartments as well as its capacity to form protein complexes were further delineated. Two dimensional gel electrophoresis showed that two forms of p16 appeared in the cytoplasm, while only one form was detected in the nucleus. Samples of basal cell carcinoma and squamous cell carcinoma of the skin with either functional or non-functional Rb also exhibited at least two forms of p16. In addition, cytoplasmic p16 bound cyclin dependent kinase (cdk)4/6, potentially indicating that p16 could have a function in the cytoplasm.

Cell Line, Tumor↗
PubMed1996

The serine protease inhibitors TLCK and TPCK react with the RB-binding core of HPV-18 E7 protein and abolish its RB-binding capability.

The human papillomaviruses associated with cervical cancer (e.g., HPV-16 and HPV-18) express an E7 oncoprotein which mediates the immortalization of primary genital keratinocytes and the transformation of rodent cells. The 105-amino-acid HPV-18 E7 protein contains two zinc fingers as well as a conserved amino-terminal motif (Rb-binding core) which binds and alters the interactions of the retinoblastoma susceptibility gene product (Rb). We report here that two serine protease inhibitors, tosyl-L-lysine chloromethyl ketone (TLCK) and tosyl-L-phenylalanine chloromethyl ketone (TPCK), reacted with and generated an altered form of the HPV-18 E7 protein. Chemical modification of the E7 protein was initially observed during its extraction and immunoprecipitation from mammalian cells but could also be detected using E7 protein expressed in vitro by reticulocyte lysates. More importantly, TLCK and TPCK were able to modify E7 protein in live keratinocytes following their addition to the culture medium. Site-specific mutagenesis demonstrated that the E7 Rb-binding core (Leu-X-Cys-X-Glu) contained a cysteine residue which was essential for this modification and that the TLCK/TPCK-dependent alteration of the E7 protein abolished its ability to bind Rb. These studies indicate that the E7 protein can be inactivated by a specific class of protease inhibitors and that such reagents may be useful for pharmacologically regulating E7 function in vivo. In addition, these results demonstrate that care must be taken when applying these commonly used protease inhibitors in experiments evaluating E7/cellular protein interactions.

Antibodies, Viral↗
PubMed1997

The mouse Spam1 maps to proximal chromosome 6 and is a candidate for the sperm dysfunction in Rb(6.16)24Lub and Rb(6.15)1Ald heterozygotes.

We have determined the chromosomal localization of the murine gene encoding the 68-kDa sperm adhesion molecule 1, Spam1 or Ph-20. Using two independent approaches, fluorescence in situ hybridization (FISH) and interspecific backcross analysis we show the Spam1 maps to proximal mouse Chromosome (Chr) 6. This map position is within the conserved linkage group corresponding to human Chr 7q, where the human homolog, SPAM 1, has been shown to map previously. Genetic mapping shows the gene to be very closely linked to Met, one of the most proximal loci on MMU 6. It thus places the gene near the centromere and the junction of the Rb(6.16)24Lub and Rb(6.15)1Ald translocations. The essential role of the Spam1 sperm antigen in mouse sperm-egg interactions and its gene location provide strong support for its candidacy as the gene involved in the dysfunction of mouse sperm bearing the Rb(6.16)24Lub or Rb(6.15)1Ald translocation.

Animals↗
PubMed1997

RB kinases and RB-binding proteins: new points of view.

The retinoblastoma protein (RB) binds to a variety of cellular proteins and suppresses cellular growth. Such interactions are regulated by phosphorylation during the cell cycle by several cyclin-dependent kinases, known as RB kinases. Clues to the specific physiological roles of different RB kinases have been obtained. Moreover, interesting functions of the RB protein, other than control of E2F activity, have been found.

Carrier Proteins↗
PubMed2002

Mixed-metal uranium(VI) iodates: hydrothermal syntheses, structures, and reactivity of Rb[UO(2)(CrO(4))(IO(3))(H(2)O)], A(2)[UO(2)(CrO(4))(IO(3))(2)] (A = K, Rb, Cs), and K(2)[UO(2)(MoO(4))(IO(3))(2)].

The reactions of the molecular transition metal iodates A[CrO(3)(IO(3))] (A = K, Rb, Cs) with UO(3) under mild hydrothermal conditions provide access to four new, one-dimensional, uranyl chromatoiodates, Rb[UO(2)(CrO(4))(IO(3))(H(2)O)] (1) and A(2)[UO(2)(CrO(4))(IO(3))(2)] (A = K (2), Rb (3), Cs (4)). Under basic conditions, MoO(3), UO(3), and KIO(4) can be reacted to form K(2)[UO(2)(MoO(4))(IO(3))(2)] (5), which is isostructural with 2 and 3. The structure of 1 consists of one-dimensional[UO(2)(CrO(4))(IO(3))(H(2)O)](-) ribbons that contain uranyl moieties bound by bridging chromate and iodate anions as well as a terminal water molecule to create [UO(7)] pentagonal bipyramidal environments around the U(VI) centers. These ribbons are separated from one another by Rb(+) cations. When the iodate content is increased in the hydrothermal reactions, the terminal water molecule is replaced by a monodentate iodate anion to yield 2-4. These ribbons can be further modified by replacing tetrahedral chromate anions with MoO(4)(2)(-) anions to yield isostructural, one-dimensional [UO(2)(MoO(4))(IO(3))(2)](2)(-) ribbons. Crystallographic data: 1, triclinic, space group P(-)1, a = 7.3133(5) A, b = 8.0561(6) A, c = 8.4870(6) A, alpha = 88.740(1) degrees, beta = 87.075(1) degrees, gamma = 71.672(1) degrees, Z = 2; 2, monoclinic, space group P2(1)/c, a = 11.1337(5) A, b = 7.2884(4) A, c = 15.5661(7) A, beta = 107.977(1) degrees, Z = 4; 3, monoclinic, space group P2(1)/c, a = 11.3463(6) A, b = 7.3263(4) A, c = 15.9332(8) A, beta = 108.173(1) degrees, Z = 4; 4, monoclinic, space group P2(1)/n, a = 7.3929(5) A, b = 8.1346(6) A, c = 22.126(2) A, beta = 90.647(1) degrees, Z = 4; 5, monoclinic, space group P2(1)/c, a = 11.3717(6) A, b = 7.2903(4) A, c = 15.7122(8) A, beta = 108.167(1) degrees, Z = 4.

Journal Article↗
PubMed2002

RB and cyclin dependent kinase pathways: defining a distinction between RB and p16 loss in lung cancer.

The genetic components of the RB:CDK:cyclin:p16 tumor suppressor pathway undergo mutational and epigenetic alterations in a wide range of human cancers and serve as critical targets for inactivation by the transforming oncoproteins of several DNA tumor viruses. Lung cancer has been a useful model system for these studies as it was the first tumor to demonstrate an important role for RB in the genesis of a common adult malignancy and was also the first human cancer to demonstrate genetic evidence for a multi-component RB:p16 tumor suppressor pathway. Lung tumorigenesis, however, is a complex disease process that requires longstanding carcinogen exposure in order to acquire somatic alterations at many distinct genetic loci. Understanding the multifunctional properties of RB to regulate cell proliferation, differentiation, and apoptosis and how they relate to the sequential accumulation of other clonal gene defects will be essential in order to understand the specific patterns of gene inactivation observed in different subtypes of lung cancer and to fulfill the promise of 'molecular target' therapeutics.

Carcinoma, Small Cell↗
PubMed1997

Selective induction of p53 and chemosensitivity in RB-deficient cells by E1A mutants unable to bind the RB-related proteins.

The adenovirus E1A oncoprotein renders primary cells sensitive to the induction of apoptosis by diverse stimuli, including many anticancer agents. E1A-expressing cells accumulate p53 protein, and p53 potentiates drug-induced apoptosis. To determine how E1A promotes chemosensitivity, a series of E1A mutants were introduced into primary human and mouse fibroblasts using high-titer recombinant retroviruses, allowing analysis of E1A in genetically normal cells outside the context of adenovirus infection. Mutations that disrupted apoptosis and chemosensitivity separated into two complementation groups, which correlated precisely with the ability of E1A to associate with either the p300/CBP or retinoblastoma protein families. Furthermore, E1A mutants incapable of binding RB, p107, and p130 conferred chemosensitivity to fibroblasts derived from RB-deficient mice, but not fibroblasts from mice lacking p107 or p130. Hence, inactivation of RB, but not p107 or p130, is required for chemosensitivity induced by E1A. Finally, the same E1A functions that promote drug-induced apoptosis also induce p53. Together, these data demonstrate that p53 accumulation and chemosensitivity are linked to E1A's oncogenic potential, and identify a strategy to selectively induce apoptosis in RB-deficient tumor cells.

Adenovirus E1A Proteins↗