Gonadotropin-regulated testicular helicase (DDX25), an essential regulator of spermatogenesis, prevents testicular germ cell apoptosis.
Gonadotropin-regulated testicular helicase (GRTH)/DDX25 is an essential post-transcriptional regulator of spermatogenesis. In GRTH null mice severe apoptosis was observed in spermatocytes entering the metaphase of meiosis. Pro- and anti-apoptotic factors were found to be under GRTH regulation in comparative studies of spermatocytes from wild type and GRTH(-/-) knock-out (KO) mice. KO mice displayed decreased levels of Bcl-2 and Bcl-xL (anti-apoptotic factors), an increase in Bid, Bak, and Bad (pro-apoptotic), reduced phospho-Bad, and release of cytochrome c. Also, an increase on Smac, a competitor of inhibitor apoptotic proteins that release caspases, was observed. These changes caused an increase in cleavage of caspases 9 and 3, activation of caspase 3 and increases in cleavage products of PARP. The half-life of caspase 3 transcripts was markedly increased in KO, indicating that GRTH had a negative role on its mRNA stability. IkappaBalpha, which sequesters NF-kappaB from its transcriptional activation of pro-apoptotic genes, was highly elevated in KO, and its phospho-form, which promotes its dissociation, was reduced. The increase of HDAC1 and abolition of p300 expression in KO indicated a nuclear action of GRTH on the NF-kappaB-mediated transcription of anti-apoptotic genes. It also regulates the associated death domain pathway and caspase 8-mediated events. GRTH-mediated apoptotic regulation was further indicated by its selective binding to pro- and anti-apoptotic mRNAs. These studies have demonstrated that GRTH, as a component of mRNP particles, acts as a negative regulator of the tumor necrosis factor receptor 1 and caspase pathways and promotes NF-kappaB function to control apoptosis in spermatocytes of adult mice.
Gutti
Ravi K
RK
Section on Molecular Endocrinology, Endocrinology and Reproduction Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4510, USA.
Tsai-Morris
Chon-Hwa
CH
Dufau
Maria L
ML
D000818:Animals; D017209:Apoptosis; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000502:physiology*; D005854:Germ Cells / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D013090:Spermatocytes / Q000378:metabolism; D013091:Spermatogenesis; D013737:Testis / Q000473:pathology; D051020:bcl-X Protein / Q000378:metabolism
D052002:NF-kappa B p50 Subunit; D019253:Proto-Oncogene Proteins c-bcl-2; D047888:Receptors, Tumor Necrosis Factor, Type I; D051020:bcl-X Protein; C073701:Nfkb1 protein, mouse; C487765:Ddx25 protein, mouse; D053487:DEAD-box RNA Helicases