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Role of PCSK5 Expression in Mouse Ovarian Follicle Development: Identification of the Inhibin α- and β-Subunits as Candidate Substrates

By Monica Antenos, Lei Lei, Min Xu, Anjali Malipatil, Sarah Kiesewetter and Teresa K. Woodruff


Inhibin and activin are essential dimeric glycoproteins belonging to the transforming growth factor-beta (TGFβ) superfamily. Inhibin is a heterodimer of α- and β-subunits, whereas activin is a homodimer of β-subunits. Production of inhibin is regulated during the reproductive cycle and requires the processing of pro-ligands to produce mature hormone. Furin is a subtilisin-like proprotein convertase (proconvertase) that activates precursor proteins by cleavage at basic sites during their transit through the secretory pathway and/or at the cell surface. We hypothesized that furin-like proconvertases are central regulators of inhibin α- and β-subunit processing within the ovary. We analyzed the expression of the proconvertases furin, PCSK5, PCSK6, and PCSK7 in the developing mouse ovary by real-time quantitative RT-PCR. The data showed that proconvertase enzymes are temporally expressed in ovarian cells. With the transition from two-layer secondary to pre-antral follicle, only PCSK5 mRNA was significantly elevated. Activin A selectively enhanced expression of PCSK5 mRNA and decreased expression of furin and PCSK6 in cultured two-layer secondary follicles. Inhibition of proconvertase enzyme activity by dec-RVKR-chloromethylketone (CMK), a highly specific and potent competitive inhibitor of subtilisin-like proconvertases, significantly impeded both inhibin α- and β-subunit maturation in murine granulosa cells. Overexpression of PC5/6 in furin-deficient cells led to increased inhibin α- and βB-subunit maturation. Our data support the role of proconvertase PCSK5 in the processing of ovarian inhibin subunits during folliculogenesis and suggest that this enzyme may be an important regulator of inhibin and activin bioavailability

Topics: Research Article
Publisher: Public Library of Science
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Provided by: PubMed Central

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  3. (1997). Activins, inhibins, and follistatins: further thoughts on a growing family of regulators.
  4. (2008). An activin/furin regulatory loop modulates the processing and secretion of inhibin alpha- and betaB-subunit dimers in pituitary gonadotrope cells.
  5. (1993). cDNA structure of the mouse and rat subtilisin/kexin-like PC5: a candidate proprotein convertase expressed in endocrine and nonendocrine cells.
  6. (1996). Characterization and determination of the biological activities of noncleavable high molecular weight forms of inhibin A and activin A.
  7. (1987). Circulating immunoreactive inhibin levels during the normal human menstrual cycle.
  8. (1989). Decreased inhibin gene expression in preovulatory follicles requires primary gonadotropin surges.
  9. (2006). Deletion of the gene encoding proprotein convertase 5/6 causes early embryonic lethality in the mouse.
  10. (2002). Disruption of PC1/ 3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects.
  11. (1988). Dynamic changes in inhibin messenger RNAs in rat ovarian follicles during the reproductive cycle.
  12. (1998). Effects of recombinant activin A on in vitro culture of mouse preantral follicles.
  13. (2006). Follicle size class contributes to distinct secretion patterns of inhibin isoforms during the rat estrous cycle.
  14. (1997). Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins.
  15. (2008). Hormonal regulation of proprotein convertase subtilisin/kexin type 5 expression during ovarian follicle development in the rat.
  16. (1993). Identification and functional expression of a new member of the mammalian Kex2-like processing endoprotease family: its striking structural similarity to PACE4.
  17. (2006). Identification of a stage-specific permissive in vitro culture environment for follicle growth and oocyte development.
  18. (1993). Identification of an isoform with an extremely large Cys-rich region of PC6, a Kex2-like processing endoprotease.
  19. (1998). Inhibin A and B secretion in mouse preantral follicle culture.
  20. (1990). Inhibin and activin locally regulate rat ovarian folliculogenesis.
  21. (2003). Local roles of TGF-beta superfamily members in the control of ovarian follicle development.
  22. (1998). Localization of prohormone convertases 1/3 and 2 in the human pituitary gland and pituitary adenomas: analysis by immunohistochemistry, immunoelectron microscopy, and laser scanning microscopy.
  23. (1991). Mammalian subtilisins: the long-sought dibasic processing endoproteases.
  24. (2007). N-linked oligosaccharides direct the differential assembly and secretion of inhibin alpha- and betaAsubunit dimers.
  25. (2007). Neonatal exposure to estrogens suppresses activin expression and signaling in the mouse ovary.
  26. (1994). Pro-protein convertases of subtilisin/kexin family.
  27. (2002). Production and purification of recombinant human inhibin and activin.
  28. (2006). Proprotein convertases: lessons from knockouts.
  29. (1990). Regulation of inhibin synthesis in the rat ovary.
  30. (2008). Regulation of Pcsk6 expression during the preantral to antral follicle transition in mice: opposing roles of FSH and oocytes.
  31. (2005). Repression of the inhibin alpha-subunit gene by the transcription factor CCAAT/enhancer-binding protein-beta.
  32. (2004). Structure and expression of Furin mRNA in the ovary of the medaka, Oryzias latipes.
  33. (2009). The mouse follicle microenvironment regulates antrum formation and steroid production: alterations in gene expression profiles.
  34. (1998). The proprotein convertases.
  35. (2000). The roles of inhibin and related peptides in gonadal function.
  36. (2006). Tissue-engineered follicles produce live, fertile offspring.