Specificity of HOX protein function depends on DNA-protein and protein-protein interactions, both mediated by the homeo domain.

Zappavigna, Vincenzo; Sartori, Daniela; Mavilio, Fulvio

doi:10.1101/gad.8.6.732

Cited by 124 publications

(120 citation statements)

References 46 publications

(56 reference statements)

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“…The functional role of the N-terminal region of homeobox proteins is largely unknown. However, Zappavigna et al 34 reported the first evidence that sequences in the N-terminal region of a HOX protein influence transcriptional activity. Interestingly, we found one patient showing overexpression of both HOXA10 and HOXA10b, which revealed a triplication of HOXA and TCRb flanking clones with deletion of the distal clones on a ring chromosome 7.…”

Section: Discussionmentioning

confidence: 99%

Clinical, cytogenetic and molecular characteristics of 14 T-ALL patients carrying the TCRβ-HOXA rearrangement: a study of the Groupe Francophone de Cytogénétique Hématologique

Cauwelier

Cavé

Gervais³

et al. 2006

Leukemia

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Recently, we and others described a new chromosomal rearrangement, that is, inv(7)(p15q34) and t(7;7)(p15;q34) involving the T-cell receptor beta (TCRb) (7q34) and the HOXA gene locus (7p15) in 5% of T-cell acute lymphoblastic leukemia (T-ALL) patients leading to transcriptional activation of especially HOXA10. To further address the clinical, immunophenotypical and molecular genetic findings of this chromosomal aberration, we studied 330 additional T-ALLs. This revealed TCRb-HOXA rearrangements in five additional patients, which brings the total to 14 cases in 424 patients (3.3%). Real-time quantitative PCR analysis for HOXA10 gene expression was performed in 170 T-ALL patients and detected HOXA10 overexpression in 25.2% of cases including all the cases with a TCRb-HOXA rearrangement (8.2%). In contrast, expression of the short HOXA10 transcript, HOXA10b, was almost exclusively found in the TCRb-HOXA rearranged cases, suggesting a specific role for the HOXA10b short transcript in TCRb-HOXA-mediated oncogenesis. Other molecular and/or cytogenetic aberrations frequently found in subtypes of T-ALL (SIL-TAL1, CALM-AF10, HOX11, HOX11L2) were not detected in the TCRb-HOXA rearranged cases except for deletion 9p21 and NOTCH1 activating mutations, which were present in 64 and 67%, respectively. In conclusion, this study defines TCRb-HOXA rearranged T-ALLs as a distinct cytogenetic subgroup by clinical, immunophenotypical and molecular genetic characteristics.

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Section: Discussionmentioning

confidence: 99%

Clinical, cytogenetic and molecular characteristics of 14 T-ALL patients carrying the TCRβ-HOXA rearrangement: a study of the Groupe Francophone de Cytogénétique Hématologique

Cauwelier

Cavé

Gervais³

et al. 2006

Leukemia

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“…This suggests the existence of other yet unidentified DNAbinding motifs within full-length HB9, which are critical for the interaction of HB9 target genes. The limited number of four genes we identified from the overlap of data sets from ChIP-onchip and gene expression analysis is a known phenomenon (38 -40) and is based on the various conditions, which are important for a specific modulation of target gene regulation (41,42). First, the gene expression is often controlled by cofactors recruited to the protein-DNA complexes as well as secondary or tertiary protein-protein interactions.…”

Section: Discussionmentioning

confidence: 99%

Homeobox Protein HB9 Binds to the Prostaglandin E Receptor 2 Promoter and Inhibits Intracellular cAMP Mobilization in Leukemic Cells

Wildenhain

Ingenhag

Rückert

et al. 2012

Journal of Biological Chemistry

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“…Six hundred micrograms of cell extract was immunoprecipitated with anti-HA antibody, anti-CDC6 antibody, or anti-HOXD13 antibody and detected by immunoblotting using anti-HA, anti-geminin, anti-CDC6, or anti-Myc antibodies. Glutathione S-transferase (GST) pulldown assays were performed as described by Zappavigna et al (66). Bacterially produced GST-HOXD13HD fusion protein and GST were immobilized on a glutathione-Sepharose 4B resin (Amersham).…”

Section: Vol 29 2009mentioning

confidence: 99%

HOXD13 Binds DNA Replication Origins To Promote Origin Licensing and Is Inhibited by Geminin

Salsi¹,

Ferrari²,

Ferraresi

et al. 2009

Molecular and Cellular Biology

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HOX DNA-binding proteins control patterning during development by regulating processes such as cell aggregation and proliferation. Recently, a possible involvement of HOX proteins in replication origin activity was suggested by results showing that a number of HOX proteins interact with the DNA replication licensing regulator geminin and bind a characterized human origin of replication. The functional significance of these observations, however, remained unclear. We show that HOXD13, HOXD11, and HOXA13 bind in vivo all characterized human replication origins tested. We furthermore show that HOXD13 interacts with the CDC6 loading factor, promotes pre-replication complex (pre-RC) proteins assembly at origins, and stimulates DNA synthesis in an in vivo replication assay. HOXD13 expression in cultured cells accelerates DNA synthesis initiation in correlation with the earlier pre-RC recruitment onto origins during G 1 phase. Geminin, which interacts with HOXD13 as well, blocks HOXD13-mediated assembly of pre-RC proteins and inhibits HOXD13-induced DNA replication. Our results uncover a function for Hox proteins in the regulation of replication origin activity and reveal an unforeseen role for the inhibition of HOX protein activity by geminin in the context of replication origin licensing.Hox proteins belong to the large family of homeodomaincontaining DNA-binding proteins. During embryonic development they control cell fates, eventually leading to the generation of different regional identities along the primary body and limb axes (17,35). Genetic analyses, including loss-and gainof-function experiments, showed that vertebrate Hox genes modulate morphogenetic processes by controlling crucial aspects such as cell proliferation and aggregation (16). This is particularly true of 5Ј HoxA and HoxD genes, which are involved in limb patterning (reviewed in references 49 and 65). The inactivation of the Hoxd13 gene in mice, for instance, causes a phenotype resulting from defects in the proliferation and/or condensation of limb mesenchymal cells (11,14).Hox proteins have been shown to act as transcription factors, which are thought to regulate sets of target genes by binding to specific DNA sequences within the transcriptional regulatory regions of these (7,33,38,43,50,51,61,62). Recent findings, however, have hinted at a possible additional function for this family of DNA-binding proteins. Hox proteins have been found to associate with the DNA replication licensing regulator geminin (39), and a number of them have been shown to bind the human LaminB2 and other origins of replication, suggesting their possible role in origin definition and/or assembly of the replication machinery (9,13,20). The functional significance of these observations, however, remained elusive.Origins of replication are poorly defined in metazoa. A consensus sequence appears not to be required for replication initiation in human cells, and only a few origins where replication initiates from a localized site in each cell cycle have been well characterize...

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Specificity of HOX protein function depends on DNA-protein and protein-protein interactions, both mediated by the homeo domain.

Abstract: [Key Words: Homeo box; homeo domain; transcriptional regulation; DNA-protein interaction; protein-protein interaction]

Cited by 124 publications

References 46 publications

Clinical, cytogenetic and molecular characteristics of 14 T-ALL patients carrying the TCRβ-HOXA rearrangement: a study of the Groupe Francophone de Cytogénétique Hématologique

Clinical, cytogenetic and molecular characteristics of 14 T-ALL patients carrying the TCRβ-HOXA rearrangement: a study of the Groupe Francophone de Cytogénétique Hématologique

Homeobox Protein HB9 Binds to the Prostaglandin E Receptor 2 Promoter and Inhibits Intracellular cAMP Mobilization in Leukemic Cells

HOXD13 Binds DNA Replication Origins To Promote Origin Licensing and Is Inhibited by Geminin

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