OTEX, an androgen-regulated human member of the paired-like class of homeobox genes

Geserick, Christoph; Weiß, Bertram; Schleuning, Wolf‐Dieter; Haendler, Bernard

doi:10.1042/bj20020399

Cited by 28 publications

(41 citation statements)

References 40 publications

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“…Over 200 homeobox transcription factors are present in mammalian species, where they take over a diverse set of roles, including control of key steps during embryogenesis (17). The RHOX transcription factors are a distinct subfamily that differs significantly from other homeobox family members, including those in the well-known HOX and POU subfamilies (12,18). The human RHOX cluster is composed of three genes located in Xq24: RHOXF1 (hPEPP1, OTEX),…”

Section: Introductionmentioning

confidence: 99%

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

Borgmann

Tüttelmann²,

Dworniczak³

et al. 2016

Hum. Mol. Genet.

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The X-linked reproductive homeobox (RHOX) gene cluster encodes transcription factors preferentially expressed in reproductive tissues. This gene cluster has important roles in male fertility based on phenotypic defects of Rhox-mutant mice and the finding that aberrant RHOX promoter methylation is strongly associated with abnormal human sperm parameters. However, little is known about the molecular mechanism of RHOX function in humans. Using gene expression profiling, we identified genes regulated by members of the human RHOX gene cluster. Some genes were uniquely regulated by RHOXF1 or RHOXF2/2B, while others were regulated by both of these transcription factors. Several of these regulated genes encode we demonstrate how the X-linked RHOX gene cluster may function in normal human spermatogenesis and we provide evidence that it is impaired in human male fertility.

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Section: Introductionmentioning

confidence: 99%

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

Borgmann

Tüttelmann²,

Dworniczak³

et al. 2016

Hum. Mol. Genet.

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“…Individual Rhox genes display unique patterns of expression during postnatal testes development and in different adult reproductive tissues, suggesting that they have unique roles in the reproductive tract (8). The human RHOX genes PEPP1/OTEX (RHOXF1) and PEPP2 (RHOXF2) are also selectively expressed in the testis, suggesting that Rhox genes have conserved roles in the reproductive tract (20,21).…”

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confidence: 99%

The RHOX5 Homeodomain Protein Mediates Transcriptional Repression of the Netrin-1 Receptor Gene Unc5c

Shanker

MacLean

et al. 2008

Journal of Biological Chemistry

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The X-linked mouse Rhox gene cluster contains more than 30 homeobox genes that are candidates to regulate multiple steps in male and female gametogenesis. The founding member of the Rhox gene cluster, Rhox5, is an androgen-dependent gene expressed in Sertoli cells that promotes the survival and differentiation of the adjacent male germ cells. Here, we report the first identification and characterization of a Rhox5-regulated gene. This gene, Unc5c, encodes a pro-apoptotic receptor with tumor suppressor activity that we found is negatively regulated by Rhox5 in the testis in vivo. Transfection analyses in cell lines of different origin indicated that Rhox5-dependent down-regulation of Unc5c requires another Sertoli cell-specific cofactor. Examination of other mouse Rhox family members revealed that mouse RHOX2 and RHOX3 also have the ability to down-regulate Unc5c expression. The human RHOX protein PEPP2 (RHOXF2) also had this ability, indicating that Unc5c repression is a conserved RHOX-dependent response. Deletion analysis identified a Rhox5-responsive element in the Unc5c 5-untranslated region. Although 5-untranslated regions typically house post-transcriptional elements, several lines of evidence indicated that Rhox5 down-regulates Unc5c at the transcriptional level. The repression of Unc5c expression by Rhox5 may, in part, mediate the pro-survival function of Rhox5 in the testis, as we found that Unc5c mutant mice have decreased germ cell apoptosis in the testis. Along with our other data, these findings led us to propose a model in which Rhox5 is a negative regulator upstream of Unc5c in a Sertoli-cell pathway that promotes germ-cell survival.Homeobox genes were originally identified as genes responsible for embryonic mutant phenotypes in Drosophila melanogaster (1). Homeobox genes have since been identified in a wide variety of eukaryotic species ranging from Saccharomyces cerevisiae to mammals (2, 3). The signature feature of all homeobox genes is a ϳ180-nt 4 motif encoding a 60-amino acid helix-turn-helix DNA-binding domain called a homeodomain that enables homeobox proteins to act as transcription factors. Homeodomain-containing transcription factors regulate a large number of embryonic developmental events, including anterior-posterior axial identity and organogenesis (4).Although the roles of homeobox transcription factors in embryonic development have been intensely studied for over two decades, their functions in controlling post-embryonic developmental events have only begun to be scrutinized. Homeobox transcription factors likely have a role in postnatal and adult developmental events because they are expressed in the cell types involved. Indeed, studies have shown that the homeobox genes HoxA9, Hoxc13, and Pdx1 are crucial for hematopoiesis, hair growth, and gut homeostasis, respectively (5-7). Another post-embryonic event that is likely regulated by homeobox genes is spermatogenesis. This idea is supported by the fact that Ͼ50 of the ϳ200 known mouse homeobox genes are expressed in the testis and...

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“…Among Rhox genes, Rhox5 (formerly named Pem) has been demonstrated to be expressed in approximately 50 to 65% of cancer cells; it has been identified as a cancer germline antigen (Wilkinson et al, 1990;Ono et al, 2000). In the human genome, three X-linked homeobox genes, RhoxF1, RhoxF2, and RhoxF2B, belong to Rhox gene family (Geserick et al, 2002;Wayne et al, 2002;Wang and Zhang, 2006). RhoxF1 and RhoxF2 are expressed in fractions of human cancer cell lines, as well as in restricted normal tissues such as testis (Wayne et al, 2002).…”

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confidence: 99%

Three Epigenetic Drugs Up-Regulate Homeobox GeneRhox5in Cancer Cells through Overlapping and Distinct Molecular Mechanisms

Bartlett²,

Gorry³

et al. 2009

Mol Pharmacol

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Epigenetic therapy of cancer using inhibitors of DNA methyltransferases (DNMT) or/and histone deacetylases (HDACs) has shown promising results in preclinical models and is being investigated in clinical trials. Homeodomain proteins play important roles in normal development and carcinogenesis. In this study, we demonstrated for the first time that an epigenetic drug could up-regulate homeobox genes in the reproductive homeobox genes on chromosome X (Rhox) family, including murine Rhox5, Rhox6, and Rhox9 and human RhoxF1 and RhoxF2 in breast, colon, and other types of cancer cells. We examined the molecular mechanisms underlining selective induction of Rhox5 in cancer cells by three epigenetic drugs: 5-aza-2Ј-deoxycytidine (DAC; decitabine), arsenic trioxide (ATO), and dine-3-ylmethoxy-carbonyl)aminomethyl]benzamide]. DAC induced Rhox5 mRNA expression from both distal promoter (Pd) and proximal promoter, whereas MS-275 and ATO induced gene expression from the Pd only. DAC and ATO inhibited both DNMT1 and DNMT3B protein expression, whereas MS-275 significantly reduced DNMT3B protein. In contrast to DAC, neither MS-275 nor ATO induced DNA demethylation on the Pd region. All three drugs led to enhanced acetylation of histones H3 and H4 at the promoter region. The occupancy of the activating histone mark dimethylated lysine 4 of H3 at Pd was enhanced by DAC and MS-275 but not ATO. Because they modulate gene expression with different potencies through shared and distinct epigenetic mechanisms, these epigenetic drugs may possess great potential in different applications for epigenetic therapy of cancer and other diseases.

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OTEX, an androgen-regulated human member of the paired-like class of homeobox genes

Cited by 28 publications

References 40 publications

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

The RHOX5 Homeodomain Protein Mediates Transcriptional Repression of the Netrin-1 Receptor Gene Unc5c

Three Epigenetic Drugs Up-Regulate Homeobox GeneRhox5in Cancer Cells through Overlapping and Distinct Molecular Mechanisms

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