Pbx Modulation of Hox Homeodomain Amino-Terminal Arms Establishes Different DNA-Binding Specificities across the<i>Hox</i>Locus

Chang, Ching-Pin; Brocchieri, Luciano; Shen, Wei; Largman, Corey; Cleary, Michael L.

doi:10.1128/mcb.16.4.1734

Cited by 273 publications

(298 citation statements)

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“…These data de®ne a minimal portion of Pbx1 that is functionally competent for induction of apoptosis and are consistent with previous (Chang et al, 1995). The required sequences¯anking the Pbx homeodomain have been proposed to mediate heterologous interactions with Hox proteins (Chang et al, 1996). Two additional constructs (1bDHD and D232 ± 430) coding for mutants that lack the Pbx homeodomain were incapable of inducing apoptosis providing further evidence that the E2a-Pbx1 chimera needs to bind DNA through its homeodomain to induce apoptosis under these experimental conditions.…”

Section: Induction Of Apoptosis By E2a-pbx1 Requires Its Function As supporting

confidence: 87%

“…A similar role for Pbx proteins is suggested by their potential involvement in a highly conserved autoregulatory loop that controls HoxB1 expression in the mouse hindbrain (Popperl et al, 1995). Recent biochemical studies support a role for Pbx/exd proteins as DNA-binding cofactors for Hox proteins (reviewed in Mann and Chan, 1996) and suggest that the binding activities of Pbx-Hox complexes contribute to the position-speci®c activities of Hox genes (Chang et al, 1996).…”

Section: Introductionmentioning

confidence: 77%

“…As summarized in Table 2, there is consistent absence of biological or transcriptional activity for minimal construct HD 232 ± 298 , which lacks the HCM, in contrast to the activity of HD 232 ± 310 which contains both the Pbx1 homeodomain and HCM. Based on mutational studies and molecular modeling (Chang et al, 1996), the HCM is predicted to serve as a site of contact for heterologous DNA-binding partners such as class I Hox proteins. Given the requirement for the HCM, we conclude that E2a-Pbx1 must function as a transcriptional protein recognizing subordinate targets in the context of heterologous DNA-binding partners to e ect apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that E2a-Pbx1 contains several domains that are necessary for its transcriptional and oncogenic properties (Chang et al, 1996;Monica et al, 1994). To assess which portions of E2a-Pbx1 are required for induction of apoptosis, we performed a structure/function analysis that utilized several mutant forms of E2a-Pbx1 whose expression was regulated by the MRE in stably transfected Reh cells.…”

Section: Induction Of Apoptosis By E2a-pbx1 Requires Its Function As mentioning

confidence: 99%

“…E2a-Pbx1 is a potent activator, whereas Pbx1 is a nonactivator, of synthetic reporter genes containing Pbx/ Hox consensus binding sites Lu et al, 1994;Van Dijk et al, 1993). Due to loss of the E2a basic DNA-binding region but retention of the Pbx homeodomain, the E2a-Pbx1 chimera displays DNAbinding properties identical to those of wild type Pbx proteins and in this capacity binds DNA cooperatively with class I Hox proteins (Chang et al, 1995(Chang et al, , 1996Lu et al, 1995;Phelan et al, 1995). These features support an hypothesis that the oncogenic properties of E2a-Pbx1 result from subversion of target genes whose expression is normally regulated by wild type Pbx proteins in the context of their role as cofactors for Hox and non-Hox homeodomain proteins.…”

Section: Introductionmentioning

confidence: 99%

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Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2

et al. 1997

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The chimeric oncoprotein E2a-Pbx1 results from fusion of the E2A and PBX1 genes following t(1;19) chromosomal translocations in B cell precursor acute leukemias. Experimentally B cell progenitors do not tolerate constitutive expression of E2a-Pbx1 which contrasts with transformation of several other cell types following its stable expression both in vitro and in vivo. To further investigate the e ects of E2a-Pbx1 on the B cell progenitors, we conditionally expressed E2a-Pbx1 under control of a metal response element in hematopoietic precursor cell lines in vitro. Inducible expression of E2a-Pbx1 resulted in cell death with the morphologic and molecular features of apoptosis. A structure-function analysis demonstrated that induction of apoptosis was not a dominant-negative e ect of the E2a moiety but, rather, required the DNA-binding homeodomain of Pbx1. E2a-Pbx1-induced apoptosis proceeded through a BCL2-responsive checkpoint eventuating in PARP inactivation but did require p53. Constitutive expression of E2a-Pbx1 did not induce apoptosis or continued cycling of Rat-1 ®broblasts in low serum conditions. These studies demonstrate that E2a-Pbx1 initiates programmed cell death of hematopoietic precursers by a mechanism that requires its chimeric transcriptional properties, but, unlike other nuclear oncoproteins, is independent of p53.

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Section: Induction Of Apoptosis By E2a-pbx1 Requires Its Function As supporting

confidence: 87%

Section: Introductionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Induction Of Apoptosis By E2a-pbx1 Requires Its Function As mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2

et al. 1997

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A Novel Pbx family member expressed during early zebrafish embryogenesis forms trimeric complexes with Meis3 and Hoxb1b

Vlachakis¹,

Ellstrom²,

Sagerström³

2000

Dev. Dyn.

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Effects ofHOX homeobox genes in blood cell differentiation

Magli¹,

1997

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The burgeoning number of articles concerning the role of HOX genes and hematopoiesis ensures that this will continue to be an area of very active research. It seems clear that HOX genes are expressed in stage- and lineage-specific patterns during early stages of hematopoietic development and differentiation. Several lines of evidence suggest that multiple genes of the HOXB (B2, B4, B6-B9), HOXC (C6, C8), and HOXA (A5) are involved in erythropoiesis. Similarly, a number of genes of the HOXA, HOXB, and HOXC appear to play a role in lymphoid cells. Furthermore, several genes, such as A9, A10, B3, B7, and B8, may control myelomonocytic differentiation. The question arises as to whether such a multiplicity of HOX genes reflects redundancy or indicates subtlety of the regulatory machinary. A similar complexity has been observed for hematopoietic cytokines, and the current view is that, although multiple molecules may have similar or overlapping effects, each factor has a specific function and regulatory combinations appear to play a critical role in controlling hematopoietic cell processes (99). One challenge for the future is to delineate in more detail the precise expression patterns of these genes in the many distinct subpopulations of blood cells and during fetal development. Overexpression of HOX genes in hematopoietic cells can dramatically perturb the differentiation of various cell lineages and can contribute to leukemogenesis. Future studies may involve the overexpression of alternatively spliced versions of different HOX genes or of truncated versions of HOX genes to ascertain the functional domains of the proteins that mediate the biologic effects. The findings in HOX knockout mice confirm a role for these genes in normal blood cell development. Further work in this area will require careful examination of fetal hematopoiesis and of animals bearing multiple HOX gene knockouts. Involvement of HOX genes in leukemia is just beginning to be appreciated. Establishing the true extent of HOX gene mutations in human disease will require strategies such as comparative genomic hybridization (100) and analysis of high density oligonucleotide arrays (101). The holy grail of homeobox work is to discover the physiologic processes and specific target genes regulated by HOX proteins. Given the broad range of tissues in which HOX genes are expressed, they would appear to be involved in very basic cellular processes, e.g., cell proliferation and death, adhesion, and migration, etc., rather than the direct regulation of tissue-specific genes. The search for target genes may be made easier by the further characterization of cooperative DNA binding between HOX proteins and other transcription factors. We speculate that HOX proteins do not behave as conventional transcriptional activators or inhibitors but rather may mark genes for potential future activation, i.e., they may establish competency to execute specific differentiation programs, with the actual activation being accomplished by transcriptional pathways triggered by exo...

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Pbx Modulation of Hox Homeodomain Amino-Terminal Arms Establishes Different DNA-Binding Specificities across theHoxLocus

Cited by 273 publications

References 83 publications

Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2

Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2

A Novel Pbx family member expressed during early zebrafish embryogenesis forms trimeric complexes with Meis3 and Hoxb1b

Effects ofHOX homeobox genes in blood cell differentiation

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