Regulation of the follicle-stimulating hormone beta gene by the LHX3 LIM-homeodomain transcription factor.
FSH is a critical hormone regulator of gonadal function that is secreted from the pituitary gonadotrope cell. Human patients and animal models with mutations in the LHX3 LIM-homeodomain transcription factor gene exhibit complex endocrine diseases, including reproductive disorders with loss of FSH. We demonstrate that in both heterologous and pituitary gonadotrope cells, specific LHX3 isoforms activate the FSH beta-subunit promoter, but not the proximal LHbeta promoter. The related LHX4 mammalian transcription factor can also induce FSHbeta promoter transcription, but the homologous Drosophila protein LIM3 cannot. The actions of LHX3 are specifically blocked by a dominant negative LHX3 protein containing a Kruppel-associated box domain. Six LHX3-binding sites were characterized within the FSHbeta promoter, including three within a proximal region that also mediates gene regulation by other transcription factors and activin. Mutations of the proximal binding sites demonstrate their importance for LHX3 induction of the FSHbeta promoter and basal promoter activity in gonadotrope cells. Using quantitative methods, we show that the responses of the FSHbeta promoter to activin do not require induction of the LHX3 gene. By comparative genomics using the human FSHbeta promoter, we demonstrate structural and functional conservation of promoter induction by LHX3. We conclude that the LHX3 LIM homeodomain transcription factor is involved in activation of the FSH beta-subunit gene in the pituitary gonadotrope cell.
Department of Biology, Indiana University-Purdue University, 723 West Michigan Street, Indianapolis, Indiana 46202-5132, USA.
Brooke E
BE
West
Gretchen E
GE
Parker
Jesse J
JJ
Savage
Parinda
P
Kiratipranon
Katherine S
KS
Toomey
Lisa R
LR
Beach
Stephanie C
SC
Colvin
Kyle W
KW
Sloop
Simon J
SJ
Rhodes
D028341:Activins / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D028322:Inhibin-beta Subunits / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D060850:LIM-Homeodomain Proteins; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010902:Pituitary Gland / Q000166:cytology / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary; D000072260:RNA Splicing Factors; D013552:Swine; D014157:Transcription Factors / Q000378:metabolism; D000097577:Homeobox Protein PITX2
D028341:Activins; D004268:DNA-Binding Proteins; D037201:Follicle Stimulating Hormone, beta Subunit; D018398:Homeodomain Proteins; D028322:Inhibin-beta Subunits; D060850:LIM-Homeodomain Proteins; D000072260:RNA Splicing Factors; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C486362:LHX4 protein, human; C094898:Lhx3 protein; C107467:SF1 protein, human; C422405:activin A