title: TEX11 modulates germ cell proliferation by competing with estrogen receptor β for the binding to HPIP.
abstract: Klinefelter syndrome (KS), characterized by the presence of more than one X-chromosome in men, is a major genetic cause of male infertility. Germ cell degeneration in KS patients is thought to be the consequences of overexpression of some genes on the X-chromosome. However, the identity of these genes and the underlying mechanisms remain unclear. Testis-expressed 11 (TEX11) is an X-chromosome-encoded germ-cell-specific protein that is expressed most abundantly in spermatogonia and early spermatocytes in the testes. In our search for TEX11-interacting partners using the yeast two-hybrid system, we identified hematopoietic pre-B cell leukemia transcription factor-interacting protein (HPIP), which anchors estrogen receptors (ER) to the cytoskeleton and modulates their functions. We found that mouse spermatogonial stem cells expressed Tex11, Hpip, and Esr2 but not Esr1. In cultured cells, TEX11 competed with ERβ for binding to HPIP. Upon treatment with 17β-estradiol or an ERβ agonist diarylpropionitrile, TEX11 promoted the nuclear translocation of ERβ and enhanced its transcriptional activities. On the other hand, TEX11 suppressed the nongenomic activities of ERβ in the cytoplasm, as indicated by reduced phosphorylation of AKT and ERK signaling molecules. Overexpression of TEX11 in mouse germ-cell-derived GC-1 and GC-2 cells suppressed the cell proliferation and the expression of cFos, Ccnd1, and Ccnb1 that were stimulated by 17β-estradiol or diarylpropionitrile and elevated the expression level of the proapoptotic Bax gene. The negative effect of TEX11 on cell proliferation suggests that increased expression of TEX11 in the germ cells may partially contribute to the spermatogenic defect observed in KS patients.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Yueh-Hsiang
authors.initials: YH
authors.lastname: Yu
authors.forename: Fong-Ping
authors.initials: FP
authors.lastname: Siao
authors.forename: Lea Chia-Ling
authors.initials: LC
authors.lastname: Hsu
authors.forename: Pauline H
authors.initials: PH
authors.lastname: Yen
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism / Q000502:physiology*; D004958:Estradiol / Q000502:physiology; D047629:Estrogen Receptor beta / Q000819:agonists / Q000378:metabolism*; D004967:Estrogens / Q000502:physiology; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007713:Klinefelter Syndrome / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011422:Propionates / Q000494:pharmacology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013093:Spermatogonia / Q000166:cytology*; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
chemical_list: C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D047629:Estrogen Receptor beta; D004967:Estrogens; D018398:Homeodomain Proteins; D009570:Nitriles; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011422:Propionates; D011506:Proteins; C000598435:TEX11 protein, human; C528721:Tex11 protein, mouse; D014157:Transcription Factors; D004958:Estradiol