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Pbx1  -  pre B cell leukemia homeobox 1

Mus musculus

Synonyms: 2310056B04Rik, AI848790, AU015730, D230003C07Rik, Homeobox protein PBX1, ...
 
 
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Disease relevance of Pbx1

  • It has been proposed that some of the oncogenic potential of E2A-Pbx1 could be mediated through heterocomplex formation with Hox proteins, which are also involved in human and mouse leukemias [1].
  • In pre B cell leukemias containing the t(1;19) chromosome translocation, Pbx1 is converted into a strong transactivator by fusion to the activation domain of the bHLH transcription factor E2A [2].
  • E2a-Pbx1 is an oncogenic derrivative of Pbx1 produced by the t(1;19) translocation in pediatric pre-B cell acute lymphoblastic leukemia [3].
  • This study suggests that perturbation of Pbx1 activity may also promote susceptibility to diabetes mellitus [4].
  • E2a/Pbx1 induces the rapid proliferation of stem cell factor-dependent murine pro-T cells that cause acute T-lymphoid or myeloid leukemias in mice [5].
 

High impact information on Pbx1

  • To investigate in vivo roles of Pbx1 in pancreatic development and function, we examined pancreatic Pbx1 expression, and morphogenesis, cell differentiation and function in mice deficient for Pbx1 [4].
  • Pbx1 is a member of the TALE (three-amino acid loop extension) class of homeodomain transcription factors, which are components of hetero-oligomeric protein complexes thought to regulate developmental gene expression and to maintain differentiated cell states [4].
  • Pbx1+/- adults had pancreatic islet malformations, impaired glucose tolerance and hypoinsulinemia [4].
  • This translocation produces a fusion gene encoding the chimeric oncoprotein E2A-Pbx1, which can induce both acute myeloid and T-lymphoid leukemia in mice [6].
  • We have identified a new PM site (PM2) and found that it cooperates with the R3 PH site to form ternary Prep1-Pbx1-Hoxb1 complexes [7].
 

Chemical compound and disease context of Pbx1

 

Biological context of Pbx1

  • The Pbx1 and Meis1 proto-oncogenes code for divergent homeodomain proteins that are targets for oncogenic mutations in human and murine leukemias, respectively, and implicated by genetic analyses to functionally collaborate with Hox proteins during embryonic development and/or oncogenesis [9].
  • Pbx1-Meis1 heterodimers display distinctive DNA binding specificities and cross-bind to a subset of Pbx-Hox sites, including those previously implicated as response elements for the execution of Pbx-dependent Hox programs in vivo [9].
  • The resulting E2a-Pbx1 chimeric proteins display potent oncogenic properties that appear to require dimerization with Hox DNA binding partners [10].
  • Pbx1 and Meis1 dimerize in solution and cooperatively bind bipartite DNA sequences consisting of directly adjacent Pbx and Meis half sites [9].
  • A current hypothesis proposes that interactions with Pbx1 are necessary for Hox proteins to regulate downstream target genes that in turn control growth, differentiation and morphogenesis during development [2].
 

Anatomical context of Pbx1

  • To define molecular pathways that may be impacted by E2a-Pbx1, a genetic screen consisting of neonatal retroviral infection was used to identify genes that accelerate development of T-cell tumors in E2A-PBX1 transgenic mice [10].
  • While stabilizing the heterodimer, the 310 helix C-terminal to the Pbx1 HD was also dispensable for the ability of E2a-Pbx1 to heterodimerize with Hox proteins and immortalize myeloblasts [3].
  • Interestingly, like Pbx1, Pbx3 is highly expressed in proliferating chondrocytes but is lost as chondrocytes become hypertrophic during endochondral ossification [11].
  • 5. During early organogenesis, until E12.5, Pbx3 expression is found mostly in the embryonic head, forelimbs, and septum transversum, unlike Pbx1 and Pbx2 expression which is more widespread [11].
  • A structural analysis of the functional domains of E2a-Pbx1 showed that portions of both E2a and Pbx1 were essential for transformation of NIH 3T3 cells and transcriptional activation of synthetic reporter genes containing PBX1 consensus binding sites [12].
 

Associations of Pbx1 with chemical compounds

 

Physical interactions of Pbx1

  • Chimeric oncoprotein E2a-Pbx1 is unable to bind DNA with Meis1, due to the deletion of amino-terminal Pbx1 sequences following fusion with E2a [9].
 

Regulatory relationships of Pbx1

  • We show that Pbx1 directly activates Pax3, leading to repression of its target gene Msx2 in NCCs [16].
 

Other interactions of Pbx1

  • We now confirm this seizure-related QTL ( Szs1) using reciprocal, interval-specific congenic strains and map it to a 6.6-Mb segment between Pbx1 and D1Mit150 [17].
  • Among these, approximately half created a Notch(IC) allele, encoding the intracellular, signaling portion of Notch1, suggesting a synergistic interaction between the Notch and E2a-Pbx1 pathways in oncogenesis [10].
  • We have used the subtractive process of representational difference analysis to identify targets of E2A-Pbx1 [2].
  • A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1 [2].
  • Finally, loss of Pbx1 markedly reduces urogenital ridge outgrowth and results in impaired differentiation of the mesonephros and kidneys and the absence of Müllerian ducts [18].
 

Analytical, diagnostic and therapeutic context of Pbx1

  • In this study, we used deletional and site-directed mutagenesis to identify portions of Pbx1 necessary for oncogenic and transcriptional activities of E2a-Pbx1 [19].
  • Taken together, these data indicate that Pbx1 is essential for the function of hematopoietic progenitors with erythropoietic potential and that its loss creates a proliferative constriction at the level of the CMP [20].
  • Accordingly, baseline proliferating cell nuclear antigen levels are lower in Pbx1(+/-) mice, and unilateral adrenalectomy results in impaired contralateral compensatory adrenal growth, indicating a lower proliferative potential in the context of Pbx1 haploinsufficiency [21].
  • When comparing gene expression, by quantitative real-time RT-PCR, in pancreatic exocrine tissue from obese non-diabetic subjects with increased islet mass, we found that Pbx-1 and Pdx-1 were up-regulated (5.9+/-1.2 and 2.4+/-0.6 versus non-obese) [22].

References

  1. The oncoprotein E2A-Pbx1a collaborates with Hoxa9 to acutely transform primary bone marrow cells. Thorsteinsdottir, U., Krosl, J., Kroon, E., Haman, A., Hoang, T., Sauvageau, G. Mol. Cell. Biol. (1999) [Pubmed]
  2. A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1. McWhirter, J.R., Goulding, M., Weiner, J.A., Chun, J., Murre, C. Development (1997) [Pubmed]
  3. An inhibitory switch derepressed by pbx, hox, and Meis/Prep1 partners regulates DNA-binding by pbx1 and E2a-pbx1 and is dispensable for myeloid immortalization by E2a-pbx1. Calvo, K.R., Knoepfler, P., McGrath, S., Kamps, M.P. Oncogene (1999) [Pubmed]
  4. Pbx1 inactivation disrupts pancreas development and in Ipf1-deficient mice promotes diabetes mellitus. Kim, S.K., Selleri, L., Lee, J.S., Zhang, A.Y., Gu, X., Jacobs, Y., Cleary, M.L. Nat. Genet. (2002) [Pubmed]
  5. E2a/Pbx1 induces the rapid proliferation of stem cell factor-dependent murine pro-T cells that cause acute T-lymphoid or myeloid leukemias in mice. Sykes, D.B., Kamps, M.P. Mol. Cell. Biol. (2004) [Pubmed]
  6. Selective repression of transcriptional activators by Pbx1 does not require the homeodomain. Lu, Q., Kamps, M.P. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  7. Hoxb1 enhancer and control of rhombomere 4 expression: complex interplay between PREP1-PBX1-HOXB1 binding sites. Ferretti, E., Cambronero, F., Tümpel, S., Longobardi, E., Wiedemann, L.M., Blasi, F., Krumlauf, R. Mol. Cell. Biol. (2005) [Pubmed]
  8. Pre-B cell leukemia transcription factor (PBX) proteins are important mediators for retinoic acid-dependent endodermal and neuronal differentiation of mouse embryonal carcinoma P19 cells. Qin, P., Haberbusch, J.M., Zhang, Z., Soprano, K.J., Soprano, D.R. J. Biol. Chem. (2004) [Pubmed]
  9. Meis proteins are major in vivo DNA binding partners for wild-type but not chimeric Pbx proteins. Chang, C.P., Jacobs, Y., Nakamura, T., Jenkins, N.A., Copeland, N.G., Cleary, M.L. Mol. Cell. Biol. (1997) [Pubmed]
  10. A carboxy-terminal deletion mutant of Notch1 accelerates lymphoid oncogenesis in E2A-PBX1 transgenic mice. Feldman, B.J., Hampton, T., Cleary, M.L. Blood (2000) [Pubmed]
  11. Spatio-temporal expression of Pbx3 during mouse organogenesis. Di Giacomo, G., Koss, M., Capellini, T.D., Brendolan, A., Pöpperl, H., Selleri, L. Gene Expr. Patterns (2006) [Pubmed]
  12. Transformation properties of the E2a-Pbx1 chimeric oncoprotein: fusion with E2a is essential, but the Pbx1 homeodomain is dispensable. Monica, K., LeBrun, D.P., Dedera, D.A., Brown, R., Cleary, M.L. Mol. Cell. Biol. (1994) [Pubmed]
  13. Estrogen-dependent E2a/Pbx1 myeloid cell lines exhibit conditional differentiation that can be arrested by other leukemic oncoproteins. Sykes, D.B., Kamps, M.P. Blood (2001) [Pubmed]
  14. Activin regulation of the follicle-stimulating hormone beta-subunit gene involves Smads and the TALE homeodomain proteins Pbx1 and Prep1. Bailey, J.S., Rave-Harel, N., McGillivray, S.M., Coss, D., Mellon, P.L. Mol. Endocrinol. (2004) [Pubmed]
  15. Cross-talk between glucocorticoid and retinoic acid signals involving glucocorticoid receptor interaction with the homoeodomain protein Pbx1. Subramaniam, N., Campión, J., Rafter, I., Okret, S. Biochem. J. (2003) [Pubmed]
  16. Pbx1 functions in distinct regulatory networks to pattern the great arteries and cardiac outflow tract. Chang, C.P., Stankunas, K., Shang, C., Kao, S.C., Twu, K.Y., Cleary, M.L. Development (2008) [Pubmed]
  17. Fine mapping of a seizure susceptibility locus on mouse Chromosome 1: nomination of Kcnj10 as a causative gene. Ferraro, T.N., Golden, G.T., Smith, G.G., Martin, J.F., Lohoff, F.W., Gieringer, T.A., Zamboni, D., Schwebel, C.L., Press, D.M., Kratzer, S.O., Zhao, H., Berrettini, W.H., Buono, R.J. Mamm. Genome (2004) [Pubmed]
  18. Pbx1 is essential for adrenal development and urogenital differentiation. Schnabel, C.A., Selleri, L., Cleary, M.L. Genesis (2003) [Pubmed]
  19. The Hox cooperativity motif of the chimeric oncoprotein E2a-Pbx1 is necessary and sufficient for oncogenesis. Chang, C.P., de Vivo, I., Cleary, M.L. Mol. Cell. Biol. (1997) [Pubmed]
  20. The Hox cofactor and proto-oncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver. DiMartino, J.F., Selleri, L., Traver, D., Firpo, M.T., Rhee, J., Warnke, R., O'Gorman, S., Weissman, I.L., Cleary, M.L. Blood (2001) [Pubmed]
  21. Pre-B-cell transcription factor 1 and steroidogenic factor 1 synergistically regulate adrenocortical growth and steroidogenesis. Lichtenauer, U.D., Duchniewicz, M., Kolanczyk, M., Hoeflich, A., Hahner, S., Else, T., Bicknell, A.B., Zemojtel, T., Stallings, N.R., Schulte, D.M., Kamps, M.P., Hammer, G.D., Scheele, J.S., Beuschlein, F. Endocrinology (2007) [Pubmed]
  22. Endocrine pancreatic tissue plasticity in obese humans is associated with cytoplasmic expression of PBX-1 in pancreatic ductal cells. Muharram, G., Beucher, A., Moerman, E., Belaïch, S., Gmyr, V., Vandewalle, B., Pattou, F., Kerr-Conte, J. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
 
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