Expression of Hoxa2 in rhombomere 4 is regulated by a conserved cross-regulatory mechanism dependent upon Hoxb1

Tümpel, Stefan; Cambronero, Francisco; Ferretti, Elisabetta; Blasi, Francesco; Wiedemann, Leanne M.; Krumlauf, Robb

doi:10.1016/j.ydbio.2006.10.029

Cited by 75 publications

(84 citation statements)

References 71 publications

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“…HOXA2, like a number of other HOX genes, is positively regulated by binding of HOX/PBX proteins to consensus sequences in the HOXA2 promoter (Tümpel et al, 2007). Hence, if HXR9 can disrupt this interaction, it should reduce HOXA2 expression, which it does ( Figure 2B).…”

Section: Disrupting the Interaction Between Hox And Pbx Triggers Apopmentioning

confidence: 99%

HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer)

et al. 2009

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The HOX genes are a family of homeodomain-containing transcription factors that determine the identity of cells and tissues during embryonic development. They are also known to behave as oncogenes in some haematological malignancies. In this study, we show that the expression of many of the HOX genes is highly elevated in primary non-small-cell lung cancers (NSCLCs) and in the derived cell lines A549 and H23. Furthermore, blocking the activity of HOX proteins by interfering with their binding to the PBX co-factor causes these cells to undergo apoptosis in vitro and reduces the growth of A549 tumours in vivo. These findings suggest that the interaction between HOX and PBX proteins is a potential therapeutic target in NSCLC. The HOX genes are a family of homeodomain-containing transcription factors that determine the identity of cells and tissues in early development (Iimura and Pourquié, 2007), and also have key regulatory roles in adult haematopoietic stem cells and their descendants (Abramovich and Humphries, 2005). In addition, HOX genes are often overexpressed in malignant cells and are known to act as oncogenes in some haematopoietic malignancies (Eklund, 2007).Repeated duplication events have given rise to 39 HOX genes in mammals, divided into four groups (A -D) in tightly linked clusters on different chromosomes (Hoegg and Meyer, 2005). The HOX genes are also divided into paralogue groups -genes that have the equivalent position in each cluster (1 -13) -thus HOXA1, for example, is the 3 0 most gene in cluster A (Scott, 1993). Whereas some HOX genes have distinct functions in specific contexts, many others have overlapping or redundant functions, both during early development (McIntyre et al, 2007) and in malignant cells (Eklund, 2007). This redundancy in HOX function is based in part upon the binding of similar DNA sequences and also on the interaction of HOX proteins with a common set of co-factors including PBX and MEIS. PBX and MEIS modify the DNA-binding specificity of HOX proteins, influence the regulation of transcription and are required for many aspects of HOX function (Moens and Selleri, 2006).In addition to haematological malignancies, the HOX genes are also expressed at high levels in many other solid malignancies, although with the exception of melanoma (Morgan et al, 2007), they are not known to have an oncogenic function. A number of studies, focusing on small groups of HOX genes, have shown that some are upregulated in lung cancer (Abe et al, 2006), but the functional significance of this is unknown. Here we present a comprehensive analysis of HOX expression in non-small-cell lung cancer (NSCLC) that reveals that many of the HOX genes have strongly elevated expression in malignant cells. Further, we show that antagonising HOX/PBX binding in the NSCLC cell lines A549 (Lieber et al, 1976) and H23 (Little et al, 1983) induces apoptosis in vitro and causes significant tumour shrinkage in A549 nude mouse models.

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Section: Disrupting the Interaction Between Hox And Pbx Triggers Apopmentioning

confidence: 99%

HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer)

et al. 2009

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“…It has been shown that the intergenic region between Hoxa2 and Hoxa3 contains conserved enhancers implicated in directing expression in r3 and r5 (r3/5) (11)(12)(13)(14) and cranial neural crest cells (ncc) (15). A conserved regulatory module located in the intron of Hoxa2 mediates expression in r4 (16). In mouse, a 7-kb (EcoRI-AatII) fragment, beginning just upstream of the first exon of Hoxa2 to the middle of the first exon of Hoxa1 (17), and a 2.5-kb (BamHI) fragment containing part of the second exon of Hoxa2 and 3Ј intergenic region (18) are capable of directing reporter activity in r2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Identification of sequence identity between multiple species alignment has been helpful in focusing in on potential regulatory elements (10,16). Therefore, we cloned, sequenced, and functionally tested the region downstream of chicken Hoxa2 gene.…”

Section: Resultsmentioning

confidence: 99%

“…In light of this conserved region surrounding the BamHI site and the important role of auto and cross-regulatory mechanisms in control of segmental Hox expression (16,(21)(22)(23)(24), we next tested whether these regions are required for activity in r2. The mouse 2.5-kb BamHI fragment was divided into two separate regions by digestion with XmnI, and each region was linked to an alkaline phosphatase (AP) reporter construct to test for regulatory activity in transgenic mice.…”

Section: Resultsmentioning

confidence: 99%

“…An enhancer has been located in a coding region of the Bcl-2 gene, although its precise sequence characteristics have not been defined (30). Recently, a Hox-Pbx responsive element has been located in the first exon of the Hoxa2 gene (31) and may work with elements located in the intron to regulate expression in r4 (16). Other types of regulatory sequences playing roles in allelic exclusion of odorant receptors (32) or alternative splicing (33) have been identified in exons and would also be subject to multiple sequence constrains.…”

Section: Discussionmentioning

confidence: 99%

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A regulatory module embedded in the coding region of Hoxa2 controls expression in rhombomere 2

Tümpel

Cambronero

Sims

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Here, we define a gene regulatory network for Hoxa2, responsible for temporal and spatial expression in hindbrain development. Hoxa2 plays an important role in regulating the regional identity of rhombomere 2 (r2) and is the only Hox gene expressed in this segment. In this study, we found that a Hoxa2 cis-regulatory module consists of five elements that direct expression in r2 of the developing hindbrain. Surprisingly, the module is imbedded in the second coding exon of Hoxa2 and therefore may be constrained by both protein coding and gene regulatory requirements. This highly conserved enhancer consists of two consensus Sox binding sites and several additional elements that act in concert to direct strong r2 specific expression. Our findings provide important insight into the regulation of segmental identity in the anterior hindbrain. Furthermore, they have broader implications in designing arrays and interpreting data from global analyses of gene regulation because regulatory input from coding regions needs to be considered.cis elements ͉ hindbrain segmentation ͉ Hox genes ͉ regulatory network

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The vertebrate Hox gene regulatory network for hindbrain segmentation: Evolution and diversification

2016

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Hindbrain development is orchestrated by a vertebrate gene regulatory network that generates segmental patterning along the anterior-posterior axis via Hox genes. Here, we review analyses of vertebrate and invertebrate chordate models that inform upon the evolutionary origin and diversification of this network. Evidence from the sea lamprey reveals that the hindbrain regulatory network generates rhombomeric compartments with segmental Hox expression and an underlying Hox code. We infer that this basal feature was present in ancestral vertebrates and, as an evolutionarily constrained developmental state, is fundamentally important for patterning of the vertebrate hindbrain across diverse lineages. Despite the common ground plan, vertebrates exhibit neuroanatomical diversity in lineage-specific patterns, with different vertebrates revealing variations of Hox expression in the hindbrain that could underlie this diversification. Invertebrate chordates lack hindbrain segmentation but exhibit some conserved aspects of this network, with retinoic acid signaling playing a role in establishing nested domains of Hox expression.

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Expression of Hoxa2 in rhombomere 4 is regulated by a conserved cross-regulatory mechanism dependent upon Hoxb1

Cited by 75 publications

References 71 publications

HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer)

HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer)

A regulatory module embedded in the coding region of Hoxa2 controls expression in rhombomere 2

The vertebrate Hox gene regulatory network for hindbrain segmentation: Evolution and diversification

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