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Gonadotropin‐Regulated Testicular Helicase (GRTH/Ddx25): A Negative Regulator of Apoptosis in Male Germ Cells
Author(s) -
Gutti Ravi Kumar,
TsaiMorris ChonHwa,
Dufau Maria L.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.648.8
Subject(s) - apoptosis , microbiology and biotechnology , caspase , biology , chemistry , transcription (linguistics) , messenger rna , gene , genetics , programmed cell death , linguistics , philosophy
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 −/− mice (KO). KO 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 GRTH negative role on its mRNA stability. IκBα, which sequesters NFκB from its transcriptional activation of pro‐apoptotic genes was highly elevated in KO, and its phospho‐form, which promotes its dissociation, was reduced. Increase of HDAC1 and abolition of p300 expression in KO indicated a nuclear action of GRTH on the NFκB‐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 antiapoptotic mRNAs. These studies have demonstrated that GRTH, as a component of mRNP particles acts as a negative regulator of the TNFR1 and Caspase pathways and promotes NFκB function to control apoptosis in spermatocytes of adult mice.