Liver receptor homolog-1 regulates the transcription of steroidogenic enzymes and induces the differentiation of mesenchymal stem cells into steroidogenic cells.
Steroidogenic factor-1 (SF-1, also known as Ad4BP) has been demonstrated to be a primary transcriptional regulator of steroidogenic-related genes. However, mRNA for liver receptor homolog-1 (LRH-1), which together with SF-1, belongs to the NR5A nuclear receptor family, is expressed at much higher levels than SF-1 mRNA in the human gonad. In our previous studies, we demonstrated that SF-1 induced the differentiation of bone marrow-derived mesenchymal stem cells (MSCs) into steroidogenic cells such as Leydig or adrenocortical cells. The introduction of LRH-1 into human MSCs (hMSCs) with the aid of cAMP also induced the expression of steroidogenic enzymes, including CYP17, and their differentiation into steroid hormone-producing cells. Promoter analysis, EMSA, and chromatin immunoprecipitation assay using LRH-1-transduced hMSCs indicated that three LRH-1 binding sites were responsible for CYP17 transactivation. Immunohistochemical studies showed that LRH-1 protein was expressed in human Leydig cells. The CYP17 promoter region was highly methylated in hMSCs, whereas it was demethylated by the introduction of LRH-1 and cAMP treatment. These results indicate that LRH-1 could represent another key regulator of the steroidogenic lineage in MSCs and play a vital role in steroid hormone production in human Leydig cells.
Department of Biochemistry, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Fukui 910-1193 Japan.
Takashi
T
Yazawa
Yoshihiko
Y
Inanoka
Tetsuya
T
Mizutani
Mayu
M
Kuribayashi
Akihiro
A
Umezawa
Kaoru
K
Miyamoto
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D000242:Cyclic AMP / Q000494:pharmacology; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006066:Gonads / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000502:physiology; D013256:Steroids / Q000096:biosynthesis*; D014161:Transduction, Genetic
D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; C539821:NR4A1 protein, human; C082631:NR5A2 protein, human; C539966:Nr0b1 protein, mouse; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D013256:Steroids; D000242:Cyclic AMP; D013254:Steroid 17-alpha-Hydroxylase