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BCR  -  breakpoint cluster region

Homo sapiens

 
 
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Disease relevance of BCR

 

Psychiatry related information on BCR

  • The breakpoint cluster region (BCR) gene is located on chromosome 22q11, one of the most significant susceptibility loci in bipolar disorder linkage studies [6].
  • Assuming that imatinib could be included in pretransplantation conditioning therapies, we tested whether combinations of imatinib and gamma-irradiation or alkylating agents such as busulfan or treosulfan would display synergistic activity in BCR-ABL-positive chronic myelogenous leukaemia BV173 and EM-3 cell lines [7].
  • The association is stronger for BCR enlargement than for VBR enlargement, suggesting that selective caudate region atrophy is associated with HIV dementia [8].
  • We found significantly elevated levels of CML in CSF of AD patients and of pentosidine in CSF of patients suffering from vascular dementia when compared to controls [9].
  • The age-dependent accumulation of CML in lens protein indicates that products of both glycation and oxidation accumulate in the lens with age, while the constant rate of accumulation of CML in lens with age argues against an age-dependent decline in free radical defense mechanisms in this tissue [10].
 

High impact information on BCR

 

Chemical compound and disease context of BCR

 

Biological context of BCR

  • The BCR-ABL story represents a notable example of how research from the fields of cytogenetics, retroviral oncology, protein phosphorylation, and small molecule chemical inhibitors can lead to the development of a successful molecular targeted therapy [11].
  • Comparing genome-wide gene expression profiles of BCR-ABL1+ pre-B ALL and normal bone marrow pre-B cells by serial analysis of gene expression, many genes involved in pre-B cell receptor signaling are silenced in the leukemia cells [3].
  • One of the important contributions of BCR to transformation is believed to be dimerization or oligomerization of ABL, thereby activating ABL tyrosine kinase activity [4].
  • Introduction of the BCR/ABL oncogene into this cell line resulted in factor-independent proliferation and constitutive phosphorylation of p95Vav [20].
  • The N-terminal sequence of the protein is derived from the BCR gene on chromosome 22 [21].
 

Anatomical context of BCR

 

Associations of BCR with chemical compounds

 

Physical interactions of BCR

  • An immune complex kinase assay showed that the 230-kDa BCR/ABL protein ahd autophosphorylation activity [25].
  • Although the biological significance of the binding remains to be uncovered, BCR binds to the XPB/p62 complex [26].
  • The amino terminal CRKL SH3 domain binds directly to a proline-rich region in the C-terminus of BCR-ABL [27].
  • These data provide evidence that BCR couples the cytoplasmic protein-tyrosine kinase and RAS signaling pathways [28].
  • SHP-1 remained attached to the BCR in subgroup Ia, but not in subgroup Ib, where signal transduction was associated with an excess of truncated CD79b [29].
 

Enzymatic interactions of BCR

  • The binding appeared to be required for XPB to be tyrosine-phosphorylated by BCR-ABL [30].
  • The SH2-SH3 domain-containing adaptor protein CRKL is the predominant tyrosine phosphorylated protein in chronic myelogenous leukemia (CML) neutrophils and BCR-ABL-expressing cell lines [27].
  • Because recent evidence has clearly implicated both PI(3,4, 5)P3 and PI(3,4)P2 in growth factor-mediated signaling, our finding that both SHIP1 and SHIP2 are constitutively tyrosine phosphorylated in CML primary hematopoietic progenitor cells may thus have important implications in p210(bcr/abl)-mediated myeloid expansion [31].
  • We have examined the ability of additional SH2 domains to bind phosphotyrosine-free BCR and compared this with their ability to bind tyrosine-phosphorylated c-ABL 1b [17].
  • Grb2 binding is mediated through a phosphorylated tyrosine residue (Y177) located within a consensus Grb2 binding site encoded by the first exon of the BCR gene [32].
 

Regulatory relationships of BCR

 

Other interactions of BCR

 

Analytical, diagnostic and therapeutic context of BCR

References

  1. BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Pendergast, A.M., Quilliam, L.A., Cripe, L.D., Bassing, C.H., Dai, Z., Li, N., Batzer, A., Rabun, K.M., Der, C.J., Schlessinger, J. Cell (1993) [Pubmed]
  2. BCR sequences essential for transformation by the BCR-ABL oncogene bind to the ABL SH2 regulatory domain in a non-phosphotyrosine-dependent manner. Pendergast, A.M., Muller, A.J., Havlik, M.H., Maru, Y., Witte, O.N. Cell (1991) [Pubmed]
  3. The BCR-ABL1 kinase bypasses selection for the expression of a pre-B cell receptor in pre-B acute lymphoblastic leukemia cells. Klein, F., Feldhahn, N., Harder, L., Wang, H., Wartenberg, M., Hofmann, W.K., Wernet, P., Siebert, R., Müschen, M. J. Exp. Med. (2004) [Pubmed]
  4. A chimeric receptor/oncogene that can be regulated by a ligand in vitro and in vivo. Okuda, K., D'Andrea, A., Etten, R.A., Griffin, J.D. J. Clin. Invest. (1997) [Pubmed]
  5. Expression of BCR/ABL and BCL-2 in myeloid progenitors leads to myeloid leukemias. Jaiswal, S., Traver, D., Miyamoto, T., Akashi, K., Lagasse, E., Weissman, I.L. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  6. The breakpoint cluster region gene on chromosome 22q11 is associated with bipolar disorder. Hashimoto, R., Okada, T., Kato, T., Kosuga, A., Tatsumi, M., Kamijima, K., Kunugi, H. Biol. Psychiatry (2005) [Pubmed]
  7. Rationale for combination therapy of chronic myelogenous leukaemia with imatinib and irradiation or alkylating agents: implications for pretransplant conditioning. Topaly, J., Fruehauf, S., Ho, A.D., Zeller, W.J. Br. J. Cancer (2002) [Pubmed]
  8. Patterns of cerebral atrophy in HIV-1-infected individuals: results of a quantitative MRI analysis. Dal Pan, G.J., McArthur, J.H., Aylward, E., Selnes, O.A., Nance-Sproson, T.E., Kumar, A.J., Mellits, E.D., McArthur, J.C. Neurology (1992) [Pubmed]
  9. Pentosidine and N(epsilon)-(carboxymethyl)-lysine in Alzheimer's disease and vascular dementia. Bär, K.J., Franke, S., Wenda, B., Müller, S., Kientsch-Engel, R., Stein, G., Sauer, H. Neurobiol. Aging (2003) [Pubmed]
  10. Oxidation of glycated proteins: age-dependent accumulation of N epsilon-(carboxymethyl)lysine in lens proteins. Dunn, J.A., Patrick, J.S., Thorpe, S.R., Baynes, J.W. Biochemistry (1989) [Pubmed]
  11. The BCR-ABL story: bench to bedside and back. Wong, S., Witte, O.N. Annu. Rev. Immunol. (2004) [Pubmed]
  12. Chromosome changes in hematologic malignancies. Larson, R.A., Golomb, H.M., Rowley, J.D. CA: a cancer journal for clinicians. (1981) [Pubmed]
  13. Cdk-Inhibitory Activity and Stability of p27(Kip1) Are Directly Regulated by Oncogenic Tyrosine Kinases. Grimmler, M., Wang, Y., Mund, T., Cilensek, Z., Keidel, E.M., Waddell, M.B., Jäkel, H., Kullmann, M., Kriwacki, R.W., Hengst, L. Cell (2007) [Pubmed]
  14. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Azam, M., Latek, R.R., Daley, G.Q. Cell (2003) [Pubmed]
  15. Loss of p53 impedes the antileukemic response to BCR-ABL inhibition. Wendel, H.G., de Stanchina, E., Cepero, E., Ray, S., Emig, M., Fridman, J.S., Veach, D.R., Bornmann, W.G., Clarkson, B., McCombie, W.R., Kogan, S.C., Hochhaus, A., Lowe, S.W. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  16. The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity. Li, S., Ilaria, R.L., Million, R.P., Daley, G.Q., Van Etten, R.A. J. Exp. Med. (1999) [Pubmed]
  17. A limited set of SH2 domains binds BCR through a high-affinity phosphotyrosine-independent interaction. Muller, A.J., Pendergast, A.M., Havlik, M.H., Puil, L., Pawson, T., Witte, O.N. Mol. Cell. Biol. (1992) [Pubmed]
  18. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Copland, M., Hamilton, A., Elrick, L.J., Baird, J.W., Allan, E.K., Jordanides, N., Barow, M., Mountford, J.C., Holyoake, T.L. Blood (2006) [Pubmed]
  19. Neutrophilic-chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with C3/A2 junction). Pane, F., Frigeri, F., Sindona, M., Luciano, L., Ferrara, F., Cimino, R., Meloni, G., Saglio, G., Salvatore, F., Rotoli, B. Blood (1996) [Pubmed]
  20. Tyrosine phosphorylation of p95Vav in myeloid cells is regulated by GM-CSF, IL-3 and steel factor and is constitutively increased by p210BCR/ABL. Matsuguchi, T., Inhorn, R.C., Carlesso, N., Xu, G., Druker, B., Griffin, J.D. EMBO J. (1995) [Pubmed]
  21. Overlapping cDNA clones define the complete coding region for the P210c-abl gene product associated with chronic myelogenous leukemia cells containing the Philadelphia chromosome. Mes-Masson, A.M., McLaughlin, J., Daley, G.Q., Paskind, M., Witte, O.N. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  22. Profiling of tyrosine phosphorylation pathways in human cells using mass spectrometry. Salomon, A.R., Ficarro, S.B., Brill, L.M., Brinker, A., Phung, Q.T., Ericson, C., Sauer, K., Brock, A., Horn, D.M., Schultz, P.G., Peters, E.C. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  23. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Mohi, M.G., Boulton, C., Gu, T.L., Sternberg, D.W., Neuberg, D., Griffin, J.D., Gilliland, D.G., Neel, B.G. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  24. The BCR gene encodes a novel serine/threonine kinase activity within a single exon. Maru, Y., Witte, O.N. Cell (1991) [Pubmed]
  25. Establishment and molecular characterization of a novel leukemic cell line with Philadelphia chromosome expressing p230 BCR/ABL fusion protein. Wada, H., Mizutani, S., Nishimura, J., Usuki, Y., Kohsaki, M., Komai, M., Kaneko, H., Sakamoto, S., Delia, D., Kanamaru, A. Cancer Res. (1995) [Pubmed]
  26. BCR binds to the xeroderma pigmentosum group B protein. Maru, Y., Kobayashi, T., Tanaka, K., Shibuya, M. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  27. CRKL binding to BCR-ABL and BCR-ABL transformation. Kolibaba, K.S., Bhat, A., Heaney, C., Oda, T., Druker, B.J. Leuk. Lymphoma (1999) [Pubmed]
  28. Tyrosine phosphorylation of BCR by FPS/FES protein-tyrosine kinases induces association of BCR with GRB-2/SOS. Maru, Y., Peters, K.L., Afar, D.E., Shibuya, M., Witte, O.N., Smithgall, T.E. Mol. Cell. Biol. (1995) [Pubmed]
  29. Role of B-cell antigen receptor-associated molecules and lipid rafts in CD5-induced apoptosis of B CLL cells. Renaudineau, Y., Nédellec, S., Berthou, C., Lydyard, P.M., Youinou, P., Pers, J.O. Leukemia (2005) [Pubmed]
  30. The BCR-ABL oncoprotein potentially interacts with the xeroderma pigmentosum group B protein. Takeda, N., Shibuya, M., Maru, Y. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  31. A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP2) is constitutively tyrosine phosphorylated and associated with src homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor cells. Wisniewski, D., Strife, A., Swendeman, S., Erdjument-Bromage, H., Geromanos, S., Kavanaugh, W.M., Tempst, P., Clarkson, B. Blood (1999) [Pubmed]
  32. Bcr phosphorylated on tyrosine 177 binds Grb2. Ma, G., Lu, D., Wu, Y., Liu, J., Arlinghaus, R.B. Oncogene (1997) [Pubmed]
  33. Co-expression with BCR induces activation of the FES tyrosine kinase and phosphorylation of specific N-terminal BCR tyrosine residues. Li, J., Smithgall, T.E. J. Biol. Chem. (1996) [Pubmed]
  34. Transcription factor BACH2 is transcriptionally regulated by the BCR/ABL oncogene. Vieira, S.A., Deininger, M.W., Sorour, A., Sinclair, P., Foroni, L., Goldman, J.M., Melo, J.V. Genes Chromosomes Cancer (2001) [Pubmed]
  35. BCR-ABL fails to inhibit apoptosis in U937 myelomonocytic cells expressing a carboxyl-terminal truncated STAT5. Ahmed, M., Dusanter-Fourt, I., Dugray, A., Dubrez, L., Novault, S., Bonnet, M.L., Gisselbrecht, S., Varet, B., Solary, E., Vainchenker, W., Turhan, A.G. Leuk. Lymphoma (2001) [Pubmed]
  36. The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. Klejman, A., Schreiner, S.J., Nieborowska-Skorska, M., Slupianek, A., Wilson, M., Smithgall, T.E., Skorski, T. EMBO J. (2002) [Pubmed]
  37. Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2. Sánchez-García, I., Grütz, G. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  38. The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins. Demiroglu, A., Steer, E.J., Heath, C., Taylor, K., Bentley, M., Allen, S.L., Koduru, P., Brody, J.P., Hawson, G., Rodwell, R., Doody, M.L., Carnicero, F., Reiter, A., Goldman, J.M., Melo, J.V., Cross, N.C. Blood (2001) [Pubmed]
  39. The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA. Baxter, E.J., Hochhaus, A., Bolufer, P., Reiter, A., Fernandez, J.M., Senent, L., Cervera, J., Moscardo, F., Sanz, M.A., Cross, N.C. Hum. Mol. Genet. (2002) [Pubmed]
  40. Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides. Aichberger, K.J., Mayerhofer, M., Krauth, M.T., Skvara, H., Florian, S., Sonneck, K., Akgul, C., Derdak, S., Pickl, W.F., Wacheck, V., Selzer, E., Monia, B.P., Moriggl, R., Valent, P., Sillaber, C. Blood (2005) [Pubmed]
  41. Mapping of four distinct BCR-related loci to chromosome region 22q11: order of BCR loci relative to chronic myelogenous leukemia and acute lymphoblastic leukemia breakpoints. Croce, C.M., Huebner, K., Isobe, M., Fainstain, E., Lifshitz, B., Shtivelman, E., Canaani, E. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  42. Cell cycle-related shifts in subcellular localization of BCR: association with mitotic chromosomes and with heterochromatin. Wetzler, M., Talpaz, M., Yee, G., Stass, S.A., Van Etten, R.A., Andreeff, M., Goodacre, A.M., Kleine, H.D., Mahadevia, R.K., Kurzrock, R. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  43. No evidence for genomic imprinting of the human BCR gene. Fioretos, T., Heisterkamp, N., Groffen, J. Blood (1994) [Pubmed]
 
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