Homeobox Transcription Factor VentX Regulates Differentiation and Maturation of Human Dendritic Cells

Wu, Xiaoming; Gao, Hong; Bleday, Ronald; Zhu, Zhongqi

doi:10.1074/jbc.m113.509158

Cited by 17 publications

(22 citation statements)

References 42 publications

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“…To explore the potential clinical relevance of the findings, we performed sequence homology search and functional analysis, which led to the identification of human homeobox protein VentX as a human homolog of Xom 12 , 13 . We found that VentX is primarily expressed in hematopoietic cells and controls proliferation and differentiation of hematopoietic cells from early ontogenesis to terminal differentiation 12 , 14 – 16 . Interestingly, comparative genomic studies showed that VentX is preserved in primates and human but lost in mice since the evolutionary divergence of rodent and primate lineages 17 .…”

Section: Introductionmentioning

confidence: 89%

The homeobox protein VentX reverts immune suppression in the tumor microenvironment

Gao

Bleday

et al. 2018

Nat Commun

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Immune suppression in the tumor microenvironment (TME) is a central obstacle to effective immunotherapy. Tumor-associated macrophages (TAMs) are key components of the TME. Although TAMs have been viewed as an ideal target of intervention to steer immunity in cancer treatment, the approach has been hampered by the lack of knowledge of how TAM plasticity is controlled by cell intrinsic factors. VentX is a homeobox protein implicated in proliferation and differentiation of human hematopoietic and immune cells. Using clinical samples obtained from cancer patients, we find that VentX expression is drastically reduced in TAMs. We show here that VentX promotes M1 differentiation of TAMs, and that VentX-regulated TAMs, in turn, revert immune suppression at the TME. Using a NSG mouse model of human colon cancers, we demonstrate that VentX regulates TAM function in tumorigenesis in vivo. Our findings suggest a mechanism underlying immune suppression at TME and potential applications of VentX-regulated TAMs in cancer immunotherapy.

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Section: Introductionmentioning

confidence: 89%

The homeobox protein VentX reverts immune suppression in the tumor microenvironment

Gao

Bleday

et al. 2018

Nat Commun

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“…C. elegans ceh-51 encodes a homeodomain-containing transcription factor that functions in mesoderm (Broitman-Maduro et al 2009). In OL1, it was called as the ortholog of VENTX, a homeodomain transcription factor that functions in the human mesodermal derivatives of the myeloid lineage (Rawat et al 2010;Wu et al 2011Wu et al , 2014Gao et al 2012). In OL2, four other C. elegans homeodomain (ceh) genes are now called as VENTX orthologs, underscoring how adjustments to the prediction programs may lead to shifts in which possible paralogs in C. elegans are called as orthologs of human genes.…”

Section: The Legacy Gene Setmentioning

confidence: 99%

OrthoList 2: A New Comparative Genomic Analysis of Human and Caenorhabditis elegans Genes

et al. 2018

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OrthoList, a compendium of Caenorhabditis elegans genes with human orthologs compiled in 2011 by a meta-analysis of four orthology-prediction methods, has been a popular tool for identifying conserved genes for research into biological and disease mechanisms. However, the efficacy of orthology prediction depends on the accuracy of gene-model predictions, an ongoing process, and orthology-prediction algorithms have also been updated over time. Here we present OrthoList 2 (OL2), a new comparative genomic analysis between C. elegans and humans, and the first assessment of how changes over time affect the landscape of predicted orthologs between two species. Although we find that updates to the orthology-prediction methods significantly changed the landscape of C. elegans-human orthologs predicted by individual programs and-unexpectedly-reduced agreement among them, we also show that our meta-analysis approach "buffered" against changes in gene content. We show that adding results from more programs did not lead to many additions to the list and discuss reasons to avoid assigning "scores" based on support by individual orthology-prediction programs; the treatment of "legacy" genes no longer predicted by these programs; and the practical difficulties of updating due to encountering deprecated, changed, or retired gene identifiers. In addition, we consider what other criteria may support claims of orthology and alternative approaches to find potential orthologs that elude identification by these programs. Finally, we created a new web-based tool that allows for rapid searches of OL2 by gene identifiers, protein domains [InterPro and SMART (Simple Modular Architecture Research Tool], or human disease associations ([OMIM (Online Mendelian Inheritence in Man], and also includes available RNA-interference resources to facilitate potential translational cross-species studies. KEYWORDS genome; homology; Caenorhabditis elegans; human S TUDIES in Caenorhabditis elegans have illuminated many mechanisms relevant to human biology and disease. Forward genetic screens based on phenotype have identified genes homologous to human disease-associated genes, illuminating fundamental properties about their roles and mechanisms of action (e.g., Greenwald 2012; Sundaram 2013; Golden 2017; van der Bliek et al. 2017). Reverse genetic methods have expanded the repertoire of possible genetic approaches. These methods include the ability to phenocopy loss-of-function mutations by feeding worms bacteria expressing double-stranded RNA (Fire et al. 1998; Timmons and Fire 1998). The efficiency of RNA interference (RNAi) in C. elegans has allowed for genome-wide screens (Fraser et al. 2000; Kamath et al. 2003; O'Reilly et al. 2016), or screens targeted to specific conserved genes, such as human disease genes (e.g., Sin et al. 2014; Vahdati Nia et al. 2017; Nordquist et al. 2018) or those involved in fundamental biological processes (e.g., Balklava et al. 2007; Dunn et al. 2010; Firnhaber and Hammarlund 2013; Allen et al. 2014; Du et al. 2015). Other...

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“…Mechanistically, we found that, similar to Xom, VentX binds to LEF/TCFs through its homeobox domain and disrupts the interaction between β‐catenin and LEF/TCFs . Consistent with its role as a canonical Wnt antagonist, recent studies from our laboratory showed that VentX plays essential role in proliferation and differentiation of hematopoietic and immune cells . As such, further exploration of the regulatory mechanisms of ubiquitin‐mediated proteolysis during early embryogenesis is likely to bring novel knowledge that is broadly implicated in immunity, cancer biology, and regenerative medicine.…”

Section: Discussionmentioning

confidence: 55%

Xom induces proteolysis of β‐catenin through GSK3β‐mediated pathway

Gao

et al. 2017

FEBS Letters

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The dorsal cell fate determination factor β-catenin and its antagonist, the ventral cell fate determination factor Xom, are expressed and distributed in a polarized fashion during early vertebrate embryogenesis. Ubiquitin-mediated proteolysis has been shown to control the abundance of both β-catenin and Xom. However, the mechanism of ubiquitin-mediated proteolysis in regulating dorsoventral patterning remains largely unclear. Our current study shows that Xom induces proteolysis of β-catenin through GSK3-mediated phosphorylation of Ser33/37 of β-catenin. Our findings reveal a novel pathway that regulates β-catenin stability, and suggest, for the first time, a critical function of ubiquitin-mediated proteolysis in balancing the integration of dorsal-ventral signals and the polarized distribution of β-catenin and Xom during dorsoventral axis formation.

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Homeobox Transcription Factor VentX Regulates Differentiation and Maturation of Human Dendritic Cells

Cited by 17 publications

References 42 publications

The homeobox protein VentX reverts immune suppression in the tumor microenvironment

The homeobox protein VentX reverts immune suppression in the tumor microenvironment

OrthoList 2: A New Comparative Genomic Analysis of Human and Caenorhabditis elegans Genes

Xom induces proteolysis of β‐catenin through GSK3β‐mediated pathway

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