Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins.

Chang, Ching Pin; Shen, Wei-Feng; Rozenfeld, Sophia; Helson, Lawrence; Largman, Corey; Cleary, Michael L.

doi:10.1101/gad.9.6.663

Cited by 373 publications

(415 citation statements)

References 53 publications

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“…In the current study, much of the HOXB4 is nuclear in both the developing and adult epidermis, particularly in hyperproliferative conditions. Our finding of substantial nuclear HOXB4 expression is consistent with both biochemical data (Chang et al, 1995;Shen et al, 1996), gene transfection studies , and transgenic animal studies (Gould et al, 1997;Popperl et al, 2000) that indicate that HOXB4 forms biologically active DNA binding complexes with PBX proteins.…”

Section: Discussionsupporting

confidence: 88%

“…HOXB4 and other HOX proteins alone exhibit weak, relatively nonspecific DNA binding (Pellerin et al, 1994;Shen et al, 1996). They gain both binding avidity and specificity by forming heterodimeric DNA binding complexes with PBX proteins (Chan et al, 1994;Chang et al, 1995;Phelan et al, 1995;Lu and Kamps, 1996). The PBX1 gene was first identified as an oncogenic fusion between the PBX homeodomain and the activation domain of the E2A gene product (Kamps et al, 1990;Nourse et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

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HOXB4 homeodomain protein is expressed in developing epidermis and skin disorders and modulates keratinocyte proliferation

Kömüves

Michael

Arbeit

et al. 2002

Developmental Dynamics

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The HOX homeodomain proteins are fundamental regulators of organ and tissue development, where they are thought to function as transcription factors, and HOX gene expression has been associated with numerous types of cancers. Previous studies have demonstrated that enforced expression of the HOXB4 protein transforms cultured fibroblasts and leads to a selective expansion of the hematopoietic stem cell pool, suggesting that this protein might play a role in cellular proliferation. In support of this concept, we now show that enforced expression of HOXB4 in human neonatal keratinocytes results in increased cellular proliferation and colony formation as well as decreased expression of the alpha-2-integrin and CD44 cell surface adhesion molecules. We previously have reported HOXB4 gene expression in the basal and suprabasal layers of developing human skin and now show extensive HOXB4 mRNA in psoriatic skin and basal cell carcinoma. In fetal human skin HOXB4 protein expression was both nuclear and cytoplasmic within epidermal basal cells and in hair follicle inner and outer root sheath cells, whereas strong nuclear signals were observed in the bulge region. In adult skin, HOXB4 protein expression was both nuclear and cytoplasmic, but was predominantly localized to the intermediate and differentiated cell layers. In contrast to the striking gradient patterns of HOX gene and protein expression previously described in developing spinal cord and limb, HOXB4 protein was uniformly detected in all regions of the fetal and adult skin. Although little HOXB4 signal localized to proliferative cell layers, as marked by proliferating cell nuclear antigen (PCNA) staining, in normal adult epidermis, nuclear HOXB4 protein expression substantially overlapped with PCNA-positive cell in a series of samples of hyperproliferative skin. Taken together, these data suggest that nuclear HOXB4 protein may play a role in the regulation of cellular proliferation/adhesion in developing fetal human epidermis and in hyperproliferation conditions, including cancers, in adult epidermis.Published 2002 Wiley-Liss, Inc. †

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

HOXB4 homeodomain protein is expressed in developing epidermis and skin disorders and modulates keratinocyte proliferation

Kömüves

Michael

Arbeit

et al. 2002

Developmental Dynamics

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“…Arguments supporting this possibility include: (i) our observations that PBX potentiates the HOX-induced proliferation and tumorigenic transformation of adult mammalian cells: (ii) the capacity of the HOX Cooperativity Motif (HCM) within E2A ± PBX to induce anchorage independent growth of ®broblasts (Chang et al, 1997); and (iii), the inability of E2A ± PBX alone to induce acute leukemia in mouse bone marrow transplantation model (Kamps and Baltimore, 1993). On the other hand, the E2A ± PBX homeodomain-independent transformation of ®broblasts (Kamps et al, 1996;Chang et al, 1997) and primary cells (Monica et al, 1994) raises question of a role for E2A ± PBX and Hox interaction in oncogenicity, since the homeodomain of PBX is necessary for cooperative DNA binding (Chang et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…A functional HOX homeodomain is indispensable for cooperative DNA-binding of HOX/PBX heterodimers (Chang et al, 1995). We next examined whether the transforming capacity of HOXB4 proteins also depends on their DNA binding ability.…”

Section: Pbx1 Enhances Tumor Growth Induced By Hoxb4mentioning

confidence: 99%

Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1

et al. 1998

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The products of PBX homeobox genes, which were initially discovered in reciprocal translocations occurring in human leukemias, have been shown to cooperate in the in vitro DNA binding with HOX proteins. Despite the growing body of data implicating Hox genes in the development of various cancers, little is known about the role of HOX ± PBX interactions in the regulation of proliferation and induction of transformation of mammalian cells. We build on the existing model of Hoxinduced transformation of Rat-1 cells to show that both cellular transformation and proliferation induced by Hoxb4 and Hoxb3 are greatly modulated by the levels of available PBX1 present in these cells. Furthermore, we show that the transforming capacity of these two HOX proteins depends on their conserved tetrapeptide and homeodomain regions which mediate binding to PBX and DNA, respectively. Taken together, results of this study demonstrate that cooperation between HOX and PBX proteins modulates cellular proliferation and strongly suggest that cooperative DNA binding by these two groups of proteins represent the basis for Hoxinduced cellular transformation.

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“…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%

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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Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins.

Cited by 373 publications

References 53 publications

HOXB4 homeodomain protein is expressed in developing epidermis and skin disorders and modulates keratinocyte proliferation

HOXB4 homeodomain protein is expressed in developing epidermis and skin disorders and modulates keratinocyte proliferation

Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1

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

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