Disease relevance of Rb1

• In contrast, retinoblastomas do not develop in Rb+/- mice [1].
• Thus, pRb functions as a direct transcriptional coactivator promoting osteoblast differentiation, which may contribute to the targeting of pRb in osteosarcoma [2].
• This cell cycle block was reversed by inactivation of Rb proteins with viral oncoproteins such as polyoma large T (PyLT) antigen and Adenovirus E1A [3].
• The retinoblastoma (RB) protein is present at low levels in early mouse embryos and in pluripotent P19 embryonal carcinoma cells; however, the levels of RB rise dramatically in neuroectoderm formed both in embryos and in differentiating cultures of P19 cells [4].
• E2F3 loss suppresses the development of the pituitary tumors that normally account for the death of Rb(+/-) mice [5].
• Under a high-fat diet, pRb-deficient (pRb(ad-/-)) mice failed to gain weight because of increased energy expenditure [6].

Psychiatry related information on Rb1

• Thus, in spite of long latency periods during which secondary alterations can accumulate, the initial loss of Rb function remains essential for tumor progression in multiple types of neuroendocrine cells [7].
• This suggests that the metabolism of the brain neurosteroids is linked to psychological stress, and Rb1 attenuates the stress-induced increase in neurosteroids [8].
• The avoidance learning of the mice in all RB-exposed A and B groups was significantly poorer than that of controls [9].

High impact information on Rb1

• Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1(+/-) animals by enhancing their differentiation [10].
• Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor [10].
• By contrast, C-cell thyroid adenomas occurring in Rb1(+/-) mice progress to metastatic medullary carcinomas after loss of Nras [10].
• We demonstrate that this indeed occurs in a mouse model of prostate cancer where epithelial cell cycle disruption via cell-specific inhibition of pRb function induces a paracrine p53 response that suppresses fibroblast proliferation in associated stroma [11].
• Combined with data from studies of conditional inactivation of Rb1 using a combination of Cre transgenic mouse lines, these results show that Rb is required in a cell-autonomous manner for appropriate exit from the cell cycle of retinal progenitor cells and for rod development [12].

Chemical compound and disease context of Rb1

• Differentiation of murine erythroleukemia cells induced by hexamethylene bisacetamide (HMBA) is associated with accumulation of underphosphorylated retinoblastoma protein (pRB) and an increase in retinoblastoma (RB) gene expression [13].
• Mutation analysis of the pRb pathway in 2',3'-dideoxycytidine- and 1, 3-butadiene-induced mouse lymphomas [14].
• However, aberrant methylation of CpG dinucleotides within the Rb-1 promoter has been depicted in certain tumors, which determines transcriptional inactivity of the gene and absence of the pRb retinoblastoma protein [15].
• The turnover rates and steady-state levels of gamma-aminobutyric acid (GABA) have been determined in 15 brain areas of three sublines of inbred mice differing in their susceptibility to audiogenic seizures: Rb3, which is seizure resistant; Rb2, which develops clonic seizures; and Rb1, which develops tonic-clonic seizures [16].
• G1 arrest of murine erythroleukemia cells induced by aphidicolin or deferoxamine is not associated with accumulation of under-phosphorylated retinoblastoma protein, suppression of cyclin A protein, or commitment of cells to terminal differentiation [17].

Biological context of Rb1

• These findings demonstrate a connection between the Rb1 family and the control of telomere length in mammalian cells [18].
• Analysis of Rb1 phosphorylation states showed prolonged hyper-phosphorylation at key developmental stages in Emd null myogenic cells, both in vivo and in vitro [19].
• Rb1 is essential for normal embryonic development, as null mice die in midgestation with widespread unscheduled cell proliferation [20].
• Cytogenetic studies demonstrated losses of 3p, 10p12, and 13q14, the latter included the Rb1 gene [21].
• The retinoblastoma tumour suppressor (Rb) pathway is believed to have a critical role in the control of cellular proliferation by regulating E2F activities [22].

Anatomical context of Rb1

• To determine whether E2F-1 deregulation--as a result of loss of pRB--promotes proliferation in vivo, we have tested whether loss of E2f1 interferes with the pituitary and thyroid tumorigenesis that occurs in Rb1(+/-) mice [23].
• We did observe increased transcriptional expression of Lap2alpha and delayed expression of Rb1, which may regulate alternative transcriptional pathways in the Lmna null myoblasts [19].
• Immunohistochemical analysis revealed the Rb1cc1 and Rb1 proteins are co-localized in the cell nuclei of NIH3T3-3 cell and various mouse tissues [24].
• We have generated an isogenic set of embryonic stem (ES) cell lines carrying single or compound loss-of-function mutations in the Rb gene family, including a cell line completely devoid of all three pocket proteins [25].
• The redundancy of the retinoblastoma proteins in vivo is reflected by the behavior of Rb-family-defective mouse embryonic fibroblasts in vitro [26].

Associations of Rb1 with chemical compounds

• This effect requires tyrosine kinase activity and the Abl C-terminus. c-Abl is localized to the cell nucleus, where it can bind DNA, and interacts with the retinoblastoma protein, a potential mediator of the growth-inhibitory effect [27].
• MEFs lacking both Rb alleles (Rb-/-) entered S phase in the presence of the dihydrofolate reductase inhibitor methotrexate [28].
• Similar changes in the RB/HBP1 ratio have been observed in normal C2 differentiation [29].
• Some euchromatic genes, targeted by the retinoblastoma protein Rb, are also believed to be regulated by histone H3 lysine 9 methylation [30].
• We found that these two pocket proteins share with Rb the ability to associate with the histone methyl transferase SUV39H1 [30].
• Further analysis on mESC maintenance or differentiation-related gene expression supports the phosphorylation at serine 788 in pRb plays a significant role for the CDK2AP1-mediated differentiation of mESCs [31].

Physical interactions of Rb1

• Various assays have demonstrated a tight correlation between the functional capacity of Rb as a growth suppressor and its ability to bind to E2F [32].
• Cyclin D mutants defective in binding to the retinoblastoma protein were impaired in rescuing mitogenic signaling [33].
• The present data demonstrate that JMJ interacts with the retinoblastoma protein (Rb), one of the master regulatory genes of cell cycle [34].
• The inhibition of MyoD family function by HBP1 required binding to RB and/or p130 [29].
• We conclude that inactivation of ARF acts more broadly than that of p53 in connecting abrogation of the Rb pathway to tumorigenesis [35].

Enzymatic interactions of Rb1

• Cyclin D-dependent kinases phosphorylate the retinoblastoma (Rb) protein and play a critical role in neuronal cell cycle control and apoptosis [36].
• RB is cleaved by caspase during apoptosis [37].
• Cyclin dependent kinase (cdk) 4 and cdk6 have historically been understood to be D-cyclin kinases that phosphorylate pRb in the nucleus to regulate G1 phase of the cell cycle [38].
• Although they had the least injury, p21-deficient mice had the highest levels of hepatic proliferation that correlated with increases in hyperphosphorylated retinoblastoma protein and Cyclin A gene expression [39].
• Cdk2/cyclin E complexes are thought to be required because they phosphorylate the retinoblastoma protein and drive cells through the G1/S transition into the S phase of the cell cycle [40].

Regulatory relationships of Rb1

• In turn, the ability of cyclin D-dependent kinases to trigger phosphorylation of the retinoblastoma (Rb) protein in the mid- to late G1 phase of the cell cycle makes the inactivation of Rb's growth suppressive function a mitogen-dependent step [41].
• Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system [42].
• There is a marked increase in p16 RNA and protein levels as primary embryo fibroblasts approach their finite lifespan in culture, but mouse p16 expression does not appear to be influenced by the status of pRb [43].
• Inhibition of retinoblastoma protein phosphorylation by myogenesis-induced changes in the subunit composition of the cyclin-dependent kinase 4 complex [44].
• Loss of Apaf-1 specifically suppressed apoptosis but not the proliferation and differentiation defects in Rb-mutant embryos [45].

Other interactions of Rb1

• In addition, the tumor-suppressor pathway Cdkn2a/Rb1 has also been implicated as a barrier to immortalization [18].
• Here we show that the E2f3 mutation completely suppresses both the inappropriate proliferation and the p53-dependent apoptosis arising in the Rb mutant embryos [46].
• E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos [46].
• Hypoxia-induced arrest is accompanied by dephosphorylation of pRb and inhibition of cyclin-dependent kinase 2, which results in part from inhibitory phosphorylation [47].
• Combined mutations of p27(-)(/)(-) and Men1(+/)(-), in contrast, did not exhibit noticeable synergistic stimulation of Rb kinase activity, cell proliferation, and tumor growth [48].

Analytical, diagnostic and therapeutic context of Rb1

• Cell cycle effects of CINK4 on tumor and normal cells were studied by flow cytometry, and changes in phosphorylation of the retinoblastoma protein (pRb), a substrate of Cdk4, were determined by western blotting [49].
• Additionally, we detected binding of both E2F1 and E2F4 to the Rb promoter in vivo using chromatin immunoprecipitation analysis on embryonic day 13.5 brain [50].
• We have used DNA microarray analysis to identify gene expression profiles in wild-type and Rb-null mouse embryo fibroblasts, as well as cells lacking other Rb family members, as an approach to developing a more complete understanding of Rb function [51].
• Mutations in the Rb-related gene RB2/p130 were detected in 11 of 14 (78.5%) primary lung tumors by single-strand conformation polymorphism and sequence analysis [52].
• Molecular cloning and developmental expression of mouse p130, a member of the retinoblastoma gene family [53].

References