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Rbl2  -  retinoblastoma-like 2

Mus musculus

Synonyms: 130 kDa retinoblastoma-associated protein, PRB2, RBR-2, Rb2, Retinoblastoma-like protein 2, ...
 
 
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Disease relevance of Rbl2

  • In Rb/p130 double mutants this hyperplasia was associated with defects in terminal differentiation of specific cell types and was dependent on the increased proliferation seen in the epithelium of mutant animals [1].
  • Pocket protein p130/Rb2 is required for efficient herpes simplex virus type 1 gene expression and viral replication [2].
  • The ability of pRb2/p130 to interact with JC virus T antigen was also studied [3].
  • Besides normal hair formation, follicular cysts, misoriented and dysplastic follicles, together with aberrant hair cycling, were also observed in the p107/p130 skin transplants [4].
  • Recent immunohistochemical studies of the retinoblastoma family of proteins in 235 specimens of lung cancer show the tightest inverse association between the histological grading in the most aggressive tumor types and pRb2/p130 [5].
 

Psychiatry related information on Rbl2

  • Recently, mutations in p130 were found to cause Warburg Micro syndrome with severe mental retardation [6].
 

High impact information on Rbl2

  • While loss of pRB causes retinoblastoma in humans and pituitary gland tumors in mice, tumorigenesis in other tissues may be suppressed by p107 and p130 [7].
  • Taken together, these findings show that p130 escorts E2F4 into the nucleus and, together with corepressor complexes that contain mSin3B and/or HDAC1, directly represses transcription from target genes as cells withdraw from the cell cycle [8].
  • The retinoblastoma protein, pRB, and the closely related proteins p107 and p130 are important regulators of the mammalian cell cycle [9].
  • To dissect the specific functions of pRB, p107, and p130 we have investigated how the expression of E2F-regulated genes is changed in cultures of primary cells lacking each of these family members [10].
  • These findings show that pRB and p107/p130 indeed provide different functions in E2F regulation and identify target genes that are dependent on pRB family proteins for their normal expression [10].
 

Chemical compound and disease context of Rbl2

  • Infection of cells with SV40, a DNA tumor virus known to abrogate formation of p130- and Rb-containing complexes, allowed dense cultures to proliferate in the presence of supraphysiological amounts of p27(kip1) but did not stimulate cell cycle traverse when cultures were cotreated with the potent cdk2 inhibitor roscovitine [11].
  • 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 [12].
  • Outer membrane proteins (OMP) extracted from both smooth (C5) and rough (Rb2) strains of Salmonella typhimurium were able to induce protective immunity to salmonellosis [13].
 

Biological context of Rbl2

 

Anatomical context of Rbl2

  • Furthermore, FGF treatment of metatarsal bone rudiments obtained from p107-/-;p130-/- embryos failed to inhibit proliferation of growth plate chondrocytes, whereas rudiments from p107-null or p130-null embryos showed only a slight inhibition of growth [17].
  • Levels of p130 mRNA vary among different adult tissues, with the highest level in testis [16].
  • Although forced expression of either p130 or pRb in mouse C2 myoblasts efficiently blocked cell cycle progression, only p130 inhibited the differentiation program [15].
  • Within testis, p130 mRNA is found predominantly in Leydig cells [16].
  • Furthermore, muscle cells overexpressing p130 had reduced levels of the muscle-promoting factor MyoD [15].
 

Associations of Rbl2 with chemical compounds

  • These protein-protein interactions are in turn regulated by carefully orchestrated phosphorylation events on multiple serine and threonine residues of pRB, p107, and p130, events which are carried out, at least in part, by the cyclin-dependent kinases that form the key elements of the cell cycle machinery [18].
  • Adult CRbL/L p130-/- mice demonstrated a threefold increase in the heart weight-to-body weight ratio and showed increased numbers of bromodeoxyuridine- and phosphorylated histone H3-positive nuclei, consistent with persistent myocyte cycling [19].
  • GABA turnover rates differ in three brain areas in Rb1 (amygdala, raphe, and hypothalamus) and in a single area (amygdala) in Rb2 when compared with Rb3 [12].
  • However, at a higher ginsenoside concentration (50 microg/ml), Rb1, Rb2, Rc, Rd, and Rf inhibited these activities [20].
  • Our results show that ginsenosides Rb2, Rc, Rd, or R2 injected supraspinally exert a antinociceptive effect in the substance P-induced pain model [21].
 

Physical interactions of Rbl2

  • However, such cells may not be representative of fully differentiated neurons, as studies with rodent brain extracts indicated that only pRB-E2F complexes and those recognized by a p130-specific serum were present [22].
  • In cycling cells p107 and p130 also interact with heterodimers comprised of Cdk2 and either A or E cyclins [22].
  • Furthermore, genotoxic stress increases the levels of nuclear E2F-4 and p130 as well as their in vivo binding to the Stathmin promoter [23].
  • In this study, we demonstrate that pRb2/p130 binds to HDAC1 [24].
  • This growth inhibition required the E2F-binding pocket domain but not the cyclin-binding domain of p130 [25].
 

Regulatory relationships of Rbl2

  • pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes [10].
  • This is the first description that p130 may have a role in inhibiting CDK activity during senescence [26].
  • The nuclear accumulation of p130 may be a novel mechanism regulating nuclear beta-catenin function during TMCH [27].
  • Rb1, and Rb2 strongly suppressed TNF-alpha production in RAW264.7 cells with an IC50 of 56.5 and 27.5 microM, respectively, and in differentiated U937 cells with an IC50 of 51.3, and 26.8 microM, respectively [28].
 

Other interactions of Rbl2

  • The three genes code for proteins, namely pRb, p107 and pRb2/p130, that share similar structures and functions [29].
  • Also, p130 is the major Rb-family protein present in E2F complexes in this sub-population of cells [15].
  • Finally, the hair abnormalities in p107/p130-null skin were associated with altered Bmp4-dependent signaling including decreased DeltaNp63 expression [4].
  • A unique domain of pRb2/p130 acts as an inhibitor of Cdk2 kinase activity [30].
  • Despite the close linkage, p130 expression appeared not to be affected by the Ft mutation [31].
 

Analytical, diagnostic and therapeutic context of Rbl2

References

  1. The related retinoblastoma (pRb) and p130 proteins cooperate to regulate homeostasis in the intestinal epithelium. Haigis, K., Sage, J., Glickman, J., Shafer, S., Jacks, T. J. Biol. Chem. (2006) [Pubmed]
  2. Pocket protein p130/Rb2 is required for efficient herpes simplex virus type 1 gene expression and viral replication. Ehmann, G.L., Burnett, H.A., Bachenheimer, S.L. J. Virol. (2001) [Pubmed]
  3. Retinoblastoma-related protein pRb2/p130 and suppression of tumor growth in vivo. Howard, C.M., Claudio, P.P., Gallia, G.L., Gordon, J., Giordano, G.G., Hauck, W.W., Khalili, K., Giordano, A. J. Natl. Cancer Inst. (1998) [Pubmed]
  4. Abnormal epidermal differentiation and impaired epithelial-mesenchymal tissue interactions in mice lacking the retinoblastoma relatives p107 and p130. Ruiz, S., Segrelles, C., Bravo, A., Santos, M., Perez, P., Leis, H., Jorcano, J.L., Paramio, J.M. Development (2003) [Pubmed]
  5. Mutations in the retinoblastoma-related gene RB2/p130 in lung tumors and suppression of tumor growth in vivo by retrovirus-mediated gene transfer. Claudio, P.P., Howard, C.M., Pacilio, C., Cinti, C., Romano, G., Minimo, C., Maraldi, N.M., Minna, J.D., Gelbert, L., Leoncini, L., Tosi, G.M., Hicheli, P., Caputi, M., Giordano, G.G., Giordano, A. Cancer Res. (2000) [Pubmed]
  6. Rab3 GTPase-activating protein regulates synaptic transmission and plasticity through the inactivation of Rab3. Sakane, A., Manabe, S., Ishizaki, H., Tanaka-Okamoto, M., Kiyokage, E., Toida, K., Yoshida, T., Miyoshi, J., Kamiya, H., Takai, Y., Sasaki, T. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130. Dannenberg, J.H., Schuijff, L., Dekker, M., van der Valk, M., te Riele, H. Genes Dev. (2004) [Pubmed]
  8. E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1/mSin3B corepressor complex. Rayman, J.B., Takahashi, Y., Indjeian, V.B., Dannenberg, J.H., Catchpole, S., Watson, R.J., te Riele, H., Dynlacht, B.D. Genes Dev. (2002) [Pubmed]
  9. Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization. Sage, J., Mulligan, G.J., Attardi, L.D., Miller, A., Chen, S., Williams, B., Theodorou, E., Jacks, T. Genes Dev. (2000) [Pubmed]
  10. pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes. Hurford, R.K., Cobrinik, D., Lee, M.H., Dyson, N. Genes Dev. (1997) [Pubmed]
  11. Density-dependent growth inhibition of fibroblasts ectopically expressing p27(kip1). Zhang, X., Wharton, W., Donovan, M., Coppola, D., Croxton, R., Cress, W.D., Pledger, W.J. Mol. Biol. Cell (2000) [Pubmed]
  12. Effect of repeated convulsive seizures on brain gamma-aminobutyric acid metabolism in three sublines of mice differing by their response to acoustic stimulations. Ciesielski, L., Simler, S., Clement, J., Mandel, P. J. Neurochem. (1987) [Pubmed]
  13. Protective immunity induced by outer membrane proteins of Salmonella typhimurium in mice. Udhayakumar, V., Muthukkaruppan, V.R. Infect. Immun. (1987) [Pubmed]
  14. Strain-dependent embryonic lethality in mice lacking the retinoblastoma-related p130 gene. LeCouter, J.E., Kablar, B., Whyte, P.F., Ying, C., Rudnicki, M.A. Development (1998) [Pubmed]
  15. The retinoblastoma-like protein p130 is involved in the determination of reserve cells in differentiating myoblasts. Carnac, G., Fajas, L., L'honoré, A., Sardet, C., Lamb, N.J., Fernandez, A. Curr. Biol. (2000) [Pubmed]
  16. Molecular cloning and developmental expression of mouse p130, a member of the retinoblastoma gene family. Chen, G., Guy, C.T., Chen, H.W., Hu, N., Lee, E.Y., Lee, W.H. J. Biol. Chem. (1996) [Pubmed]
  17. FGF signaling targets the pRb-related p107 and p130 proteins to induce chondrocyte growth arrest. Laplantine, E., Rossi, F., Sahni, M., Basilico, C., Cobrinik, D. J. Cell Biol. (2002) [Pubmed]
  18. Dissecting functions of the retinoblastoma tumor suppressor and the related pocket proteins by integrating genetic, cell biology, and electrophoretic techniques. Hansen, K., Lukas, J., Holm, K., Kjerulff, A.A., Bartek, J. Electrophoresis (1999) [Pubmed]
  19. Overlapping roles of pocket proteins in the myocardium are unmasked by germ line deletion of p130 plus heart-specific deletion of Rb. MacLellan, W.R., Garcia, A., Oh, H., Frenkel, P., Jordan, M.C., Roos, K.P., Schneider, M.D. Mol. Cell. Biol. (2005) [Pubmed]
  20. In vitro effect of standardized ginseng extracts and individual ginsenosides on the catalytic activity of human CYP1A1, CYP1A2, and CYP1B1. Chang, T.K., Chen, J., Benetton, S.A. Drug Metab. Dispos. (2002) [Pubmed]
  21. Antinociceptive effects of ginsenosides injected intracerebroventricularly or intrathecally in substance P-induced pain model. Choi, S.S., Han, E.J., Han, K.J., Lee, H.K., Suh, H.W. Planta Med. (2003) [Pubmed]
  22. Characterization of transcription factor E2F complexes during muscle and neuronal differentiation. Corbeil, H.B., Whyte, P., Branton, P.E. Oncogene (1995) [Pubmed]
  23. E2F mediates sustained G2 arrest and down-regulation of Stathmin and AIM-1 expression in response to genotoxic stress. Polager, S., Ginsberg, D. J. Biol. Chem. (2003) [Pubmed]
  24. The COOH-terminal region of pRb2/p130 binds to histone deacetylase 1 (HDAC1), enhancing transcriptional repression of the E2F-dependent cyclin A promoter. Stiegler, P., De Luca, A., Bagella, L., Giordano, A. Cancer Res. (1998) [Pubmed]
  25. Control of retinoblastoma protein-independent hematopoietic cell cycle by the pRB-related p130. Hoshikawa, Y., Mori, A., Amimoto, K., Iwabe, K., Hatakeyama, M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  26. Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1. Collado, M., Medema, R.H., Garcia-Cao, I., Dubuisson, M.L., Barradas, M., Glassford, J., Rivas, C., Burgering, B.M., Serrano, M., Lam, E.W. J. Biol. Chem. (2000) [Pubmed]
  27. Epithelial proliferation induces novel changes in APC expression. Umar, S., Wang, Y., Sellin, J.H. Oncogene (2005) [Pubmed]
  28. In vitro inhibitory effect of protopanaxadiol ginsenosides on tumor necrosis factor (TNF)-alpha production and its modulation by known TNF-alpha antagonists. Cho, J.Y., Yoo, E.S., Baik, K.U., Park, M.H., Han, B.H. Planta Med. (2001) [Pubmed]
  29. The RB-related gene Rb2/p130 in neuroblastoma differentiation and in B-myb promoter down-regulation. Raschellà, G., Tanno, B., Bonetto, F., Negroni, A., Claudio, P.P., Baldi, A., Amendola, R., Calabretta, B., Giordano, A., Paggi, M.G. Cell Death Differ. (1998) [Pubmed]
  30. A unique domain of pRb2/p130 acts as an inhibitor of Cdk2 kinase activity. De Luca, A., MacLachlan, T.K., Bagella, L., Dean, C., Howard, C.M., Claudio, P.P., Baldi, A., Khalili, K., Giordano, A. J. Biol. Chem. (1997) [Pubmed]
  31. Ft1, a novel gene related to ubiquitin-conjugating enzymes, is deleted in the Fused toes mouse mutation. Lesche, R., Peetz, A., van der Hoeven, F., Rüther, U. Mamm. Genome (1997) [Pubmed]
  32. The retinoblastoma gene family is differentially expressed during embryogenesis. Jiang, Z., Zacksenhaus, E., Gallie, B.L., Phillips, R.A. Oncogene (1997) [Pubmed]
  33. p130 is dispensable in peripheral T lymphocytes: evidence for functional compensation by p107 and pRB. Mulligan, G.J., Wong, J., Jacks, T. Mol. Cell. Biol. (1998) [Pubmed]
  34. Vascular ligation response is independent of p107: stressing the role of the related p130. Sindermann, J.R., Köbbert, C., Bauer, F., Skaletz-Rorowski, A., Hohage, H., Plenz, G., Breithardt, G., March, K.L. Am. J. Physiol. Heart Circ. Physiol. (2003) [Pubmed]
 
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