Conditional immortalization of mouse myelomonocytic, megakaryocytic and mast cell progenitors by the Hox-2.4 homeobox gene.

Perkins, Andrew; Cory, Suzanne

doi:10.1002/j.1460-2075.1993.tb06062.x

Cited by 105 publications

(68 citation statements)

References 60 publications

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“…Similar observations were found for the IL-3-dependent Hoxb-8/Hox2.4-induced transformation (Perkins and Cory, 1993). The other important conclusion from this study is that combined inhibition of mitogenic and survival pathways is necessary to block anchorage-independent growth of IEC-6/Cdx1 cells.…”

Section: Discussionsupporting

confidence: 88%

Homeobox gene Cdx1 regulates Ras, Rho and PI3 kinase pathways leading to transformation and tumorigenesis of intestinal epithelial cells

et al. 2001

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The Cdx1 homeobox gene encodes for an intestinespeci®c transcription factor involved in the control of proliferation and dierentiation of epithelial cells. Although it has been indicated that Cdx1 may act as a proto-oncogene in cultured ®broblasts, its direct role in the regulation of intestinal tumorigenesis has not been demonstrated. Here we show that expression of Cdx1 in an intestinal epithelial cell line (IEC-6) induces anchorage-independent growth in soft agar and promotes the formation of adenocarcinoma in vivo. The phenotype of Cdx1-induced tumors was exacerbated when IEC-6/ Cdx1 cells were injected together with matrigel containing mitogens and extracellular matrix components. These changes were correlated with an increase in the GTPbound form of Ras, modulation of Cdc42 and Rho-A activities, and accumulation of phosphatidyl inositol 3 (PI3) kinase products. Moreover, combined inhibition of Ras/Rho and PI3 kinase signaling by syntethic inhibitors blocked colony formation of IEC-6/Cdx1 cells in soft agar. Taken together, these results demonstrate a direct involvement of Cdx1, and its collaboration with Ras, Rho and PI3 kinase pathways, in transformation and tumorigenesis of intestinal epithelial cells. Oncogene (2001) 20, 4180 ± 4187.

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Section: Discussionsupporting

confidence: 88%

Homeobox gene Cdx1 regulates Ras, Rho and PI3 kinase pathways leading to transformation and tumorigenesis of intestinal epithelial cells

et al. 2001

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“…A subset of Hox genes is oncogenically activated by similar mechanisms in murine and human myeloid leukemias (3,4,21,34,35). It is unclear how ectopic Meis1 expression contributes to leukemogenesis, particularly since deregulated expression of Hox proteins alone is sufficient for induction of transformed phenotypes in experimental models (29,42,51). The oncogenic properties of Meis1 remain uncharacterized, and it hasn't been determined whether ectopic expression of Meis1 alone results in oncogenic changes or whether it facilitates transformation only within the context of coexpressed Hox proteins.…”

Section: Discussionmentioning

confidence: 99%

Meis Proteins are Major In Vivo DNA Binding Partners for Wild-Type but Not Chimeric Pbx Proteins

Chang

Jacobs

Nakamura

et al. 1997

Molecular and Cellular Biology

241

263

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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. Although Pbx proteins have been shown to dimerize with Hox proteins and modulate their DNA binding properties in vitro, the biochemical compositions of endogenous Pbx-containing complexes have not been determined. In the present study, we demonstrate that Pbx and Meis proteins form abundant complexes that comprise a major Pbx-containing DNA binding activity in nuclear extracts of cultured cells and mouse embryos. Pbx1 and Meis1 dimerize in solution and cooperatively bind bipartite DNA sequences consisting of directly adjacent Pbx and Meis half sites. 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. Chimeric oncoprotein E2a-Pbx1 is unable to bind DNA with Meis1, due to the deletion of amino-terminal Pbx1 sequences following fusion with E2a. We conclude that Meis proteins are preferred in vivo DNA binding partners for wild-type Pbx1, a relationship that is circumvented by its oncogenic counterpart E2a-Pbx1.Hox proteins make critical contributions to cell fate and segmental patterning during embryonic development (30). As targets of oncogenic mutations in human and murine leukemias, they are also implicated in cancer pathogenesis (3,4,21,34,35), which likely reflects perturbations of their roles in normal hematopoietic cell differentiation (23). In these capacities, they are presumed to function as transcription factors whose DNA binding activities are mediated through a conserved motif known as the homeodomain, which is structurally related to the bacterial helix-turn-helix motif (48). However, at a molecular level, the contributions of Hox proteins to developmental processes and disease pathogenesis are inadequately explained, given their disappointingly poor in vitro DNA binding affinities and specificities as monomeric proteins. This has led to the proposal that additional factors are required to modulate the DNA binding and transcriptional properties of Hox proteins (13), which would be consistent with models for achievement of specificity by other classes of transcriptional proteins.Genetic and biochemical studies support the argument for a role for members of the Pbx, exd, and ceh-20 subfamily (5) of divergent homeodomain proteins as potential Hox cofactors. In Drosophila melanogaster, exd is required for the execution of genetic programs that are also dependent on Hox proteins for appropriate segment-specific expression (40,45,46). A similar role for mammalian Pbx proteins is suggested by genetic analyses demonstrating that sequence elements with features of Pbx-Hox consensus sites are required for appropriate expression of murine Hoxb-1 in th...

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“…For example, mouse BM cells, overexpressing HOXB8 as a result of retroviral transfection, had enhanced capacity to form IL-3-dependent cell lines. 174 Furthermore, an increase was noted in self-renewal of early clonogenic cells, concomitant with expansion of progenitor cells and a propensity to evolve into leukemia.…”

Section: Functional Analysis Of Hox Gene Expression In Normal Hematopmentioning

confidence: 99%

The role of Homeobox genes in normal hematopoiesis and hematological malignancies

et al. 1999

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In the last decade it has become clear that homeobox containing genes (HOX genes) not only play a significant role in regulating body formation, but in addition, they are contributing to organization and regulation of hematopoiesis. Modern molecular technologies showed that deregulated expression or disruption of Hox genes can lead to altered characteristics of blood cells or disturbance of blood cell development. In this paper we review the role of HOX proteins in hematopoiesis and leukemogenesis and speculate about their possible target genes and involvement in lymphomagenesis.

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Conditional immortalization of mouse myelomonocytic, megakaryocytic and mast cell progenitors by the Hox-2.4 homeobox gene.

Cited by 105 publications

References 60 publications

Homeobox gene Cdx1 regulates Ras, Rho and PI3 kinase pathways leading to transformation and tumorigenesis of intestinal epithelial cells

Homeobox gene Cdx1 regulates Ras, Rho and PI3 kinase pathways leading to transformation and tumorigenesis of intestinal epithelial cells

Meis Proteins are Major In Vivo DNA Binding Partners for Wild-Type but Not Chimeric Pbx Proteins

The role of Homeobox genes in normal hematopoiesis and hematological malignancies

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