title: PCSK6 regulated by LH inhibits the apoptosis of human granulosa cells via activin A and TGFβ2.
abstract: Mammalian proprotein convertases (PCs) play an important role in folliculogenesis, as they proteolytically activate a variety of substrates such as the transforming growth factor beta (TGFβ) superfamily. PC subtilism/kexin 6 (PCSK6) is a member of the PC family and is ubiquitously expressed and implicated in many physiological and pathological processes. However, in human granulosa cells, the expression of the PC family members, their hormonal regulation, and the function of PCs are not clear. In this study, we found that PCSK6 is the most highly expressed PC family member in granulosa cells. LH increased PCSK6 mRNA level and PCSK6 played an anti-apoptosis function in KGN cells. Knockdown of PCSK6 not only increased the secretion of activin A and TGFβ2 but also decreased the secretion of follistatin, estrogen, and the mRNA levels of FSH receptor (FSHR) and P450AROM (CYP19A1). We also found that, in the KGN human granulosa cell line, TGFβ2 and activin A could promote the apoptosis of KGN cells and LH could regulate the follistatin level. These data indicate that PCSK6, which is regulated by LH, is highly expressed in human primary granulosa cells of pre-ovulatory follicles and plays important roles in regulating a series of downstream molecules and apoptosis of KGN cells.
authors.affiliation: Laboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, No. 413, Zhaozhou Road, Shanghai 200011, ChinaShanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai 200011, ChinaDepartment of Reproductive MedicineShanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 536, Changle Road, Shanghai 200040, ChinaLaboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, No. 413, Zhaozhou Road, Shanghai 200011, ChinaShanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai 200011, ChinaDepartment of Reproductive MedicineShanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 536, Changle Road, Shanghai 200040, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Laboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, No. 413, Zhaozhou Road, Shanghai 200011, ChinaShanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai 200011, ChinaDepartment of Reproductive MedicineShanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 536, Changle Road, Shanghai 200040, ChinaLaboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, No. 413, Zhaozhou Road, Shanghai 200011, ChinaShanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai 200011, ChinaDepartment of Reproductive MedicineShanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 536, Changle Road, Shanghai 200040, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Wang
authors.affiliation: Laboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, No. 413, Zhaozhou Road, Shanghai 200011, ChinaShanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai 200011, ChinaDepartment of Reproductive MedicineShanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 536, Changle Road, Shanghai 200040, ChinaLaboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, No. 413, Zhaozhou Road, Shanghai 200011, ChinaShanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai 200011, ChinaDepartment of Reproductive MedicineShanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 536, Changle Road, Shanghai 200040, China.
authors.forename: Deng-Xuan
authors.initials: DX
authors.lastname: Fan
authors.affiliation: Laboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, No. 413, Zhaozhou Road, Shanghai 200011, ChinaShanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai 200011, ChinaDepartment of Reproductive MedicineShanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 536, Changle Road, Shanghai 200040, ChinaLaboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, No. 413, Zhaozhou Road, Shanghai 200011, ChinaShanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai 200011, ChinaDepartment of Reproductive MedicineShanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 536, Changle Road, Shanghai 200040, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, No. 413, Zhaozhou Road, Shanghai 200011, ChinaShanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai 200011, ChinaDepartment of Reproductive MedicineShanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 536, Changle Road, Shanghai 200040, ChinaLaboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, No. 413, Zhaozhou Road, Shanghai 200011, ChinaShanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai 200011, ChinaDepartment of Reproductive MedicineShanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 536, Changle Road, Shanghai 200040, China.
authors.forename: Ming-Qing
authors.initials: MQ
authors.lastname: Li
authors.affiliation: Laboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, No. 413, Zhaozhou Road, Shanghai 200011, ChinaShanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai 200011, ChinaDepartment of Reproductive MedicineShanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 536, Changle Road, Shanghai 200040, China jinliping2012@gmail.com whx595@163.com.
authors.forename: Hai-Xia
authors.initials: HX
authors.lastname: Wu
authors.affiliation: Laboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, No. 413, Zhaozhou Road, Shanghai 200011, ChinaShanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai 200011, ChinaDepartment of Reproductive MedicineShanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 536, Changle Road, Shanghai 200040, ChinaLaboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, No. 413, Zhaozhou Road, Shanghai 200011, ChinaShanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai 200011, ChinaDepartment of Reproductive MedicineShanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 536, Changle Road, Shanghai 200040, China jinliping2012@gmail.com whx595@163.com.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Jin
mesh_terms: D028341:Activins / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001141:Aromatase / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004967:Estrogens / Q000378:metabolism; D005260:Female; D038681:Follistatin / Q000378:metabolism; D006107:Granulosa Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007986:Luteinizing Hormone / Q000494:pharmacology*; D043484:Proprotein Convertases / Q000187:drug effects* / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011962:Receptors, FSH / Q000378:metabolism; D012697:Serine Endopeptidases / Q000187:drug effects* / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004967:Estrogens; D038681:Follistatin; D012333:RNA, Messenger; D011962:Receptors, FSH; D053781:Transforming Growth Factor beta2; C422405:activin A; D028341:Activins; D007986:Luteinizing Hormone; D001141:Aromatase; C561410:CYP19A1 protein, human; C080654:PCSK6 protein, human; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: LH; PCSK6; TGFβ2; activin A; apoptosis; granulosa cells