Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2002 Aug 15;366(Pt 1):367–375. doi: 10.1042/BJ20020399

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

Christoph Geserick 1, Bertram Weiss 1, Wolf-Dieter Schleuning 1, Bernard Haendler 1
PMCID: PMC1222745  PMID: 11980563

Abstract

paired genes emerged early in evolution and code for homeobox transcription factors, having fundamental roles in various biological processes. We identified a novel human member of the paired-like class, which we named OTEX. A phylogenetic analysis revealed that OTEX belonged to the recently defined PEPP subfamily of paired-like homeobox genes. It was organized into three introns and, like the other PEPP genes, it was mapped to chromosome X. Its transcripts were detected mainly in the ovary, testis and epididymis, but also in the prostate and mammary gland. In the PC-3/ARwt prostate cell line, OTEX expression was stimulated dramatically following androgen treatment. Immunofluorescence studies revealed an exclusively nuclear localization of the OTEX protein. Mutation of the RARCRRHQRE amino acid sequence present at the C-terminus of the OTEX homeodomain resulted in a mainly cytoplasmic localization, indicating that this motif harboured the nuclear localization signal. No inherent transactivation function was seen for OTEX using the one-hybrid assay, and no homodimer formation was observed in the two-hybrid assay, suggesting that additional partners were needed for this activity. Taken together, the data show that OTEX represents a novel, androgen-regulated, paired-like homeobox protein, with possibly an important role in human reproduction.

Full Text

The Full Text of this article is available as a PDF (312.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barbulescu K., Geserick C., Schüttke I., Schleuning W. D., Haendler B. New androgen response elements in the murine pem promoter mediate selective transactivation. Mol Endocrinol. 2001 Oct;15(10):1803–1816. doi: 10.1210/mend.15.10.0708. [DOI] [PubMed] [Google Scholar]
  2. Beverdam A., Brouwer A., Reijnen M., Korving J., Meijlink F. Severe nasal clefting and abnormal embryonic apoptosis in Alx3/Alx4 double mutant mice. Development. 2001 Oct;128(20):3975–3986. doi: 10.1242/dev.128.20.3975. [DOI] [PubMed] [Google Scholar]
  3. Birk O. S., Casiano D. E., Wassif C. A., Cogliati T., Zhao L., Zhao Y., Grinberg A., Huang S., Kreidberg J. A., Parker K. L. The LIM homeobox gene Lhx9 is essential for mouse gonad formation. Nature. 2000 Feb 24;403(6772):909–913. doi: 10.1038/35002622. [DOI] [PubMed] [Google Scholar]
  4. Boulikas T. Putative nuclear localization signals (NLS) in protein transcription factors. J Cell Biochem. 1994 May;55(1):32–58. doi: 10.1002/jcb.240550106. [DOI] [PubMed] [Google Scholar]
  5. Branford W. W., Zhao G. Q., Valerius M. T., Weinstein M., Birkenmeier E. H., Rowe L. B., Potter S. S. Spx1, a novel X-linked homeobox gene expressed during spermatogenesis. Mech Dev. 1997 Jul;65(1-2):87–98. doi: 10.1016/s0925-4773(97)00058-0. [DOI] [PubMed] [Google Scholar]
  6. Breathnach R., Chambon P. Organization and expression of eucaryotic split genes coding for proteins. Annu Rev Biochem. 1981;50:349–383. doi: 10.1146/annurev.bi.50.070181.002025. [DOI] [PubMed] [Google Scholar]
  7. Dasen J. S., Martinez Barbera J. P., Herman T. S., Connell S. O., Olson L., Ju B., Tollkuhn J., Baek S. H., Rose D. W., Rosenfeld M. G. Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis. Genes Dev. 2001 Dec 1;15(23):3193–3207. doi: 10.1101/gad.932601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fei Y., Hughes T. E. Nuclear trafficking of photoreceptor protein crx: the targeting sequence and pathologic implications. Invest Ophthalmol Vis Sci. 2000 Sep;41(10):2849–2856. [PubMed] [Google Scholar]
  9. Fohn L. E., Behringer R. R. ESX1L, a novel X chromosome-linked human homeobox gene expressed in the placenta and testis. Genomics. 2001 May 15;74(1):105–108. doi: 10.1006/geno.2001.6532. [DOI] [PubMed] [Google Scholar]
  10. Fromental-Ramain C., Warot X., Lakkaraju S., Favier B., Haack H., Birling C., Dierich A., Doll e P., Chambon P. Specific and redundant functions of the paralogous Hoxa-9 and Hoxd-9 genes in forelimb and axial skeleton patterning. Development. 1996 Feb;122(2):461–472. doi: 10.1242/dev.122.2.461. [DOI] [PubMed] [Google Scholar]
  11. Galliot B., de Vargas C., Miller D. Evolution of homeobox genes: Q50 Paired-like genes founded the Paired class. Dev Genes Evol. 1999 Mar;209(3):186–197. doi: 10.1007/s004270050243. [DOI] [PubMed] [Google Scholar]
  12. Gehring W. J., Affolter M., Bürglin T. Homeodomain proteins. Annu Rev Biochem. 1994;63:487–526. doi: 10.1146/annurev.bi.63.070194.002415. [DOI] [PubMed] [Google Scholar]
  13. Gendron R. L., Paradis H., Hsieh-Li H. M., Lee D. W., Potter S. S., Markoff E. Abnormal uterine stromal and glandular function associated with maternal reproductive defects in Hoxa-11 null mice. Biol Reprod. 1997 May;56(5):1097–1105. doi: 10.1095/biolreprod56.5.1097. [DOI] [PubMed] [Google Scholar]
  14. Haendler B. Androgen-selective gene regulation in the prostate. Biomed Pharmacother. 2002 Mar;56(2):78–83. doi: 10.1016/s0753-3322(01)00159-7. [DOI] [PubMed] [Google Scholar]
  15. Han Y. J., Lee Y. H., Chun J. Y. Identification and characterization of Psx-2, a novel member of the Psx (placenta-specific homeobox) family. Gene. 2000 Jan 4;241(1):149–155. doi: 10.1016/s0378-1119(99)00453-9. [DOI] [PubMed] [Google Scholar]
  16. Han Y. J., Park A. R., Sung D. Y., Chun J. Y. Psx, a novel murine homeobox gene expressed in placenta. Gene. 1998 Jan 30;207(2):159–166. doi: 10.1016/s0378-1119(97)00620-3. [DOI] [PubMed] [Google Scholar]
  17. Jans D. A., Xiao C. Y., Lam M. H. Nuclear targeting signal recognition: a key control point in nuclear transport? Bioessays. 2000 Jun;22(6):532–544. doi: 10.1002/(SICI)1521-1878(200006)22:6<532::AID-BIES6>3.0.CO;2-O. [DOI] [PubMed] [Google Scholar]
  18. Krauss C. M., Turksoy R. N., Atkins L., McLaughlin C., Brown L. G., Page D. C. Familial premature ovarian failure due to an interstitial deletion of the long arm of the X chromosome. N Engl J Med. 1987 Jul 16;317(3):125–131. doi: 10.1056/NEJM198707163170301. [DOI] [PubMed] [Google Scholar]
  19. Li Y., Behringer R. R. Esx1 is an X-chromosome-imprinted regulator of placental development and fetal growth. Nat Genet. 1998 Nov;20(3):309–311. doi: 10.1038/3129. [DOI] [PubMed] [Google Scholar]
  20. Li Y., Lemaire P., Behringer R. R. Esx1, a novel X chromosome-linked homeobox gene expressed in mouse extraembryonic tissues and male germ cells. Dev Biol. 1997 Aug 1;188(1):85–95. doi: 10.1006/dbio.1997.8640. [DOI] [PubMed] [Google Scholar]
  21. Lo K., Smale S. T. Generality of a functional initiator consensus sequence. Gene. 1996 Dec 5;182(1-2):13–22. doi: 10.1016/s0378-1119(96)00438-6. [DOI] [PubMed] [Google Scholar]
  22. Maiti S., Doskow J., Li S., Nhim R. P., Lindsey J. S., Wilkinson M. F. The Pem homeobox gene. Androgen-dependent and -independent promoters and tissue-specific alternative RNA splicing. J Biol Chem. 1996 Jul 19;271(29):17536–17546. doi: 10.1074/jbc.271.29.17536. [DOI] [PubMed] [Google Scholar]
  23. Maiti S., Doskow J., Sutton K., Nhim R. P., Lawlor D. A., Levan K., Lindsey J. S., Wilkinson M. F. The Pem homeobox gene: rapid evolution of the homeodomain, X chromosomal localization, and expression in reproductive tissue. Genomics. 1996 Jun 15;34(3):304–316. doi: 10.1006/geno.1996.0291. [DOI] [PubMed] [Google Scholar]
  24. Maiti S., Meistrich M. L., Wilson G., Shetty G., Marcelli M., McPhaul M. J., Morris P. L., Wilkinson M. F. Irradiation selectively inhibits expression from the androgen-dependent Pem homeobox gene promoter in sertoli cells. Endocrinology. 2001 Apr;142(4):1567–1577. doi: 10.1210/endo.142.4.8076. [DOI] [PubMed] [Google Scholar]
  25. Miller D. J., Hayward D. C., Reece-Hoyes J. S., Scholten I., Catmull J., Gehring W. J., Callaerts P., Larsen J. E., Ball E. E. Pax gene diversity in the basal cnidarian Acropora millepora (Cnidaria, Anthozoa): implications for the evolution of the Pax gene family. Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4475–4480. doi: 10.1073/pnas.97.9.4475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Moede T., Leibiger B., Pour H. G., Berggren P., Leibiger I. B. Identification of a nuclear localization signal, RRMKWKK, in the homeodomain transcription factor PDX-1. FEBS Lett. 1999 Nov 19;461(3):229–234. doi: 10.1016/s0014-5793(99)01446-5. [DOI] [PubMed] [Google Scholar]
  27. Norris R. A., Kern M. J. Identification of domains mediating transcription activation, repression, and inhibition in the paired-related homeobox protein, Prx2 (S8). DNA Cell Biol. 2001 Feb;20(2):89–99. doi: 10.1089/104454901750070292. [DOI] [PubMed] [Google Scholar]
  28. Pitman J. L., Lin T. P., Kleeman J. E., Erickson G. F., MacLeod C. L. Normal reproductive and macrophage function in Pem homeobox gene-deficient mice. Dev Biol. 1998 Oct 15;202(2):196–214. doi: 10.1006/dbio.1998.8978. [DOI] [PubMed] [Google Scholar]
  29. Rao E., Weiss B., Fukami M., Rump A., Niesler B., Mertz A., Muroya K., Binder G., Kirsch S., Winkelmann M. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet. 1997 May;16(1):54–63. doi: 10.1038/ng0597-54. [DOI] [PubMed] [Google Scholar]
  30. Sasaki A. W., Doskow J., MacLeod C. L., Rogers M. B., Gudas L. J., Wilkinson M. F. The oncofetal gene Pem encodes a homeodomain and is regulated in primordial and pre-muscle stem cells. Mech Dev. 1991 Jun;34(2-3):155–164. doi: 10.1016/0925-4773(91)90052-8. [DOI] [PubMed] [Google Scholar]
  31. Satokata I., Benson G., Maas R. Sexually dimorphic sterility phenotypes in Hoxa10-deficient mice. Nature. 1995 Mar 30;374(6521):460–463. doi: 10.1038/374460a0. [DOI] [PubMed] [Google Scholar]
  32. Swanson W. J., Clark A. G., Waldrip-Dail H. M., Wolfner M. F., Aquadro C. F. Evolutionary EST analysis identifies rapidly evolving male reproductive proteins in Drosophila. Proc Natl Acad Sci U S A. 2001 Jun 12;98(13):7375–7379. doi: 10.1073/pnas.131568198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Takasaki N., McIsaac R., Dean J. Gpbox (Psx2), a homeobox gene preferentially expressed in female germ cells at the onset of sexual dimorphism in mice. Dev Biol. 2000 Jul 1;223(1):181–193. doi: 10.1006/dbio.2000.9741. [DOI] [PubMed] [Google Scholar]
  34. Takasaki N., Rankin T., Dean J. Normal gonadal development in mice lacking GPBOX, a homeobox protein expressed in germ cells at the onset of sexual dimorphism. Mol Cell Biol. 2001 Dec;21(23):8197–8202. doi: 10.1128/MCB.21.23.8197-8202.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Tanaka M., Schinke M., Liao H. S., Yamasaki N., Izumo S. Nkx2.5 and Nkx2.6, homologs of Drosophila tinman, are required for development of the pharynx. Mol Cell Biol. 2001 Jul;21(13):4391–4398. doi: 10.1128/MCB.21.13.4391-4398.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Torres M., Gómez-Pardo E., Dressler G. R., Gruss P. Pax-2 controls multiple steps of urogenital development. Development. 1995 Dec;121(12):4057–4065. doi: 10.1242/dev.121.12.4057. [DOI] [PubMed] [Google Scholar]
  37. Treisman J., Harris E., Wilson D., Desplan C. The homeodomain: a new face for the helix-turn-helix? Bioessays. 1992 Mar;14(3):145–150. doi: 10.1002/bies.950140302. [DOI] [PubMed] [Google Scholar]
  38. Wimmer Katharina, Zhu Xx Xiao-xiang, Rouillard Jean Marie, Ambros Peter F., Lamb Barbara J., Kuick Rork, Eckart Markus, Weinhäusl Andreas, Fonatsch Christa, Hanash Sam M. Combined restriction landmark genomic scanning and virtual genome scans identify a novel human homeobox gene, ALX3, that is hypermethylated in neuroblastoma. Genes Chromosomes Cancer. 2002 Mar;33(3):285–294. doi: 10.1002/gcc.10030. [DOI] [PubMed] [Google Scholar]
  39. Wuyts W., Cleiren E., Homfray T., Rasore-Quartino A., Vanhoenacker F., Van Hul W. The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500). J Med Genet. 2000 Dec;37(12):916–920. doi: 10.1136/jmg.37.12.916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Yan Y. T., Stein S. M., Ding J., Shen M. M., Abate-Shen C. A novel PF/PN motif inhibits nuclear localization and DNA binding activity of the ESX1 homeoprotein. Mol Cell Biol. 2000 Jan;20(2):661–671. doi: 10.1128/mcb.20.2.661-671.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Zellmer E., Zhang Z., Greco D., Rhodes J., Cassel S., Lewis E. J. A homeodomain protein selectively expressed in noradrenergic tissue regulates transcription of neurotransmitter biosynthetic genes. J Neurosci. 1995 Dec;15(12):8109–8120. doi: 10.1523/JNEUROSCI.15-12-08109.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES