Description | GRTH contains three ATG in frame codons with the potential for generation of multiple protein species (61/56, 48/43 and 33 kDa) (Sheng et al., 2003). The 61/56 kDa proteins are the major species observed in the human testis (Tang et al., 1999; Tsai-Morris et al., 2007). GRTH 56- and 61-kDa species are present in nucleus and cytoplasm (Sheng et al., 2006), respectively. Based on the mouse model, the 56 kDa nuclear species interacts with CRM1 and participates in mRNA transport in the human testis and the phosphorylated 61 kDa species associates with mRNAs at polysomal sites and also within the Chromatoid Body of round spermatids. |
Expression | GRTH (484 aa) is highly expressed in the testis: somatic (Leydig cells) and germinal (meiotic spermatocytes, round spermatids and elongated spermatids) cells (Sheng et al., 2003; Tsai-Morris, et al., 2004). GRTH is genetically close to DBP5/DDX19b (63% overall aa homology) involved in mRNA export (Schmitt et al., 1999). |
Localisation | GRTH is localized in the nucleus and at cytoplasmic sites in polyribosomes and the Chromatoid Body (CB) of round spermatids (Tsai-Morris et al., 2004; Sheng et al., 2006; Sato et al., 2010; Tsai-Morris et al., 2012). |
Function | GRTH is a multifunctional protein essential for completion of spermatogenesis as a post-transcriptional regulator of relevant genes during germ cells development (Tsai-Morris et al., 2004; Sheng et al., 2006; Dufau and Tsai-Morris, 2007; Tsai-Morris et al., 2010). It contains ATPase activity (ATP/Mg dependent), and is a bi-directional RNA helicase. As a translational regulator it participates in the in vitro and in vivo translation of RNA templates. GRTH is a shuttling protein that exports germ cell specific RNA as mRNP particles from nucleus to cytoplasm via the CRM1-dependent pathway. A specific set of testicular gene transcripts, including those of chromatin-remodeling proteins (Tp1 and Tp2, Prm1 and PRM2), cytoskeletal structural proteins (Fsc1/Odf1) and tACE are associated with GRTH protein. GRTH also selectively binds mRNAs of pro-apoptotic and anti-apoptotic genes, the death receptor and proteins involved in the NF-kB pathways to mediate anti-apoptotic regulation (Gutti et al., 2008). GRTH is required to maintain the structural integrity of the chromatoid body (storage/processing organelle of mRNAs that contains members of the small miRNA RISC-complex) during spermatogenesis (Sato et al., 2010). GRTH also participates in the regulation of microRNA biogenesis in germ cells (Dai et al., 2011) and associates with polyribosome for translational initiation of target genes. In Leydig cells, GRTH prevents overstimulation of gonadotropin-induced androgen pathway by promoting degradation of StAR protein (Fukushima et al., 2011). |
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| Model of GRTH action in male germ cells during development (derived from mouse studies). 56 kDa GRTH species enters the nucleus (1), where it binds messages and associates with CRM1 (2) as mRNP complex to export messages through nuclear pores via the CRM1 pathway to the cytoplasm (3a) and to the chromatoid body (CB), either directly (via nuclear pores adjacent to or associated with the CB) (3b) or indirectly via the cytoplasmic route (4b). It is phosphorylated at cytoplasmic sites, and participates in translation at polyribosomes (4a). In the CB, messages are potentially regulated via si/mi/pi RNA pathway (5a and b). Stored messages are subsequently translated in polyribosomes (4a and 6) at specific times during spermatogenesis. |
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Single nucleotide polymorphisms of the gonadotrophin-regulated testicular helicase (GRTH) gene may be associated with the human spermatogenesis impairment. |
A Z, Zhang S, Yang Y, Ma Y, Lin L, Zhang W. |
Hum Reprod. 2006 Mar;21(3):755-9. Epub 2005 Nov 17. |
PMID 16293649 |
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Testis-specific miRNA-469 up-regulated in gonadotropin-regulated testicular RNA helicase (GRTH/DDX25)-null mice silences transition protein 2 and protamine 2 messages at sites within coding region: implications of its role in germ cell development. |
Dai L, Tsai-Morris CH, Sato H, Villar J, Kang JH, Zhang J, Dufau ML. |
J Biol Chem. 2011 Dec 30;286(52):44306-18. Epub 2011 Nov 15. |
PMID 22086916 |
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Gonadotropin-regulated testicular helicase (GRTH/DDX25): a master post-transcriptional regulator of spermatogenesis. |
Dufau ML, Sato H, Gutti R, Tsai-Morris CH. |
Adv Exp Med Biol. 2011;707:23-9. |
PMID 21691948 |
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Gonadotropin-regulated testicular helicase (GRTH/DDX25): an essential regulator of spermatogenesis. |
Dufau ML, Tsai-Morris CH. |
Trends Endocrinol Metab. 2007 Oct;18(8):314-20. Epub 2007 Sep 21. (REVIEW) |
PMID 17889551 |
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Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25), a negative regulator of luteinizing/chorionic gonadotropin hormone-induced steroidogenesis in Leydig cells: central role of steroidogenic acute regulatory protein (StAR). |
Fukushima M, Villar J, Tsai-Morris CH, Dufau ML. |
J Biol Chem. 2011 Aug 26;286(34):29932-40. Epub 2011 Jun 30. |
PMID 21719703 |
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Gonadotropin-regulated testicular helicase (DDX25), an essential regulator of spermatogenesis, prevents testicular germ cell apoptosis. |
Gutti RK, Tsai-Morris CH, Dufau ML. |
J Biol Chem. 2008 Jun 20;283(25):17055-64. Epub 2008 Apr 22. |
PMID 18430733 |
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Relevance of gonadotropin-regulated testicular RNA helicase (GRTH/DDX25) in the structural integrity of the chromatoid body during spermatogenesis. |
Sato H, Tsai-Morris CH, Dufau ML. |
Biochim Biophys Acta. 2010 May;1803(5):534-43. Epub 2010 Feb 20. |
PMID 20176059 |
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Dbp5, a DEAD-box protein required for mRNA export, is recruited to the cytoplasmic fibrils of nuclear pore complex via a conserved interaction with CAN/Nup159p. |
Schmitt C, von Kobbe C, Bachi A, Pante N, Rodrigues JP, Boscheron C, Rigaut G, Wilm M, Seraphin B, Carmo-Fonseca M, Izaurralde E. |
EMBO J. 1999 Aug 2;18(15):4332-47. |
PMID 10428971 |
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Gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25) is a transport protein involved in gene-specific mRNA export and protein translation during spermatogenesis. |
Sheng Y, Tsai-Morris CH, Gutti R, Maeda Y, Dufau ML. |
J Biol Chem. 2006 Nov 17;281(46):35048-56. Epub 2006 Sep 12. |
PMID 16968703 |
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A novel gonadotropin-regulated testicular RNA helicase. A new member of the dead-box family. |
Tang PZ, Tsai-Morris CH, Dufau ML. |
J Biol Chem. 1999 Dec 31;274(53):37932-40. |
PMID 10608860 |
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Role of Gonadotropin Regulated Testicular RNA Helicase (GRTH/DDX25) on Polysomal Associated mRNAs in Mouse Testis. |
Tsai-Morris CH, Sato H, Gutti R, Dufau ML. |
PLoS One. 2012;7(3):e32470. Epub 2012 Mar 30. |
PMID 22479328 |
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Androgen-Induced Activation of Gonadotropin-Regulated Testicular RNA Helicase (GRTH/Ddx25) Transcription: Essential Role of a Nonclassical Androgen Response Element Half-Site. |
Villar J, Tsai-Morris CH, Dai L, Dufau ML. |
Mol Cell Biol. 2012 Apr;32(8):1566-80. Epub 2012 Feb 13. |
PMID 22331472 |
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