Human chorionic gonadotropin up-regulates expression of myeloid cell leukemia-1 protein in human granulosa-lutein cells: implication of corpus luteum rescue and ovarian hyperstimulation syndrome.
BACKGROUND
The corpus luteum is a dynamic endocrine structure with periodic development and regression during menstrual cycles. Its lifespan can be prolonged by human chorionic gonadotropin (hCG). However, the signal mechanisms of this phenomenon remain unclear.


OBJECTIVE
Our objective was to investigate the molecular mechanisms of hCG in the maintenance of the viability of granulosa-lutein cells.


METHODS
Granulosa-lutein cells were obtained from women undergoing in vitro fertilization. We examined the effects of hCG on the survival of cultured granulosa-lutein cells. The signal pathway inducing antiapoptotic protein was investigated.


RESULTS
hCG enhanced viability of granulosa-lutein cells through antiapoptosis but not proliferation, because the apoptotic marker of annexin V was decreased, but the proliferative markers of Ki67 and proliferating cell nuclear antigen were not increased. Myeloid cell leukemia-1 (Mcl-1) protein, but not B-cell lymphoma protein-2 or B-cell lymphoma protein-xL, was significantly induced by hCG and LH. The granulosa-lutein cells secreted vascular endothelial growth factor that induced endothelial permeability. Mcl-1 small interfering RNA increased DNA fragmentation and diminished the antiapoptotic effect of hCG. hCG induced Mcl-1 expression through the LH/hCG receptor, adenylate cyclase, protein kinase A, and cAMP response element-binding protein signal pathway. Flavopiridol inhibited Mcl-1 production, released cytochrome c, and induced apoptosis of granulosa-lutein cells.


CONCLUSIONS
We first demonstrate that hCG prevents apoptosis of granulosa-lutein cells through the induction of Mcl-1 protein via the LH/hCG receptor and a cAMP response element-binding protein-dependent pathway. We may have found the molecular mechanism for luteal rescue during early pregnancy. Mcl-1 prevents apoptosis and increases cell viability but not proliferation as mechanisms for luteal rescue. Mcl-1 is a key molecule of hCG signaling.
Chen
Shee-Uan
SU
Department of Obstetrics and Gynecology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan.
Chen
Ruey-Jien
RJ
Shieh
Jeng-Yi
JY
Chou
Chia-Hung
CH
Lin
Chung-Wu
CW
Lu
Hsin-Fen
HF
Yang
Yu-Shih
YS
D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D003338:Corpus Luteum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D008184:Luteal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016471:Ovarian Hyperstimulation Syndrome / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D011974:Receptors, LH / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D006063:Chorionic Gonadotropin; D005419:Flavonoids; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D011974:Receptors, LH; C077990:alvocidib