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Bone morphogenetic protein 2 (BMP2) ...

Ho, Catherine C.

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Bone morphogenetic protein 2 (BMP2) regulates follicle-stimulating hormone beta subunit (Fshb) expression in gonadotrope cells.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Bone morphogenetic protein 2 (BMP2) regulates follicle-stimulating hormone beta subunit (Fshb) expression in gonadotrope cells./
Author:	Ho, Catherine C.
Description:	240 p.
Notes:	Source: Dissertation Abstracts International, Volume: 72-09, Section: B, page: .
Contained By:	Dissertation Abstracts International72-09B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=NR74527
ISBN:	9780494745274

Bone morphogenetic protein 2 (BMP2) regulates follicle-stimulating hormone beta subunit (Fshb) expression in gonadotrope cells.
Ho, Catherine C.

Bone morphogenetic protein 2 (BMP2) regulates follicle-stimulating hormone beta subunit (Fshb) expression in gonadotrope cells. - 240 p.

Source: Dissertation Abstracts International, Volume: 72-09, Section: B, page: .

Thesis (Ph.D.)--McGill University (Canada), 2011.

Proper follicle-stimulating hormone (FSH) synthesis, secretion, and action are required for normal reproductive function in mammals. A major goal of our lab and of this thesis is to reveal the intracellular mechanisms controlling FSH synthesis. The expression of the Fshb subunit gene (Fshb) is rate-limiting in production of the mature dimeric hormone and is regulated by numerous endocrine hormones and paracrine acting factors, including gonadotropin-releasing hormone, sex steroids, and transforming growth factor beta (TGFbeta) superfamily ligands such as activins. Recent studies suggest that bone morphogenetic proteins (BMPs), a sub-family of TGFbeta family ligands, also regulate Fshb transcription. BMP2 and BMP4 were further observed to stimulate Fshb transcription synergistically with activins. Here, I used the immortalized murine gonadotrope cell line, LbetaT2, to investigate mechanisms by which BMP2 regulates Fshb gene expression. I determined that BMP2 acts through the BMP receptors BMPR1A and BMPR2 to stimulate Fshb transcription. The data suggest that BMP2's effect on Fshb expression is more significant when acting synergistically with activins, and appears to depend on BMP-stimulated gene expression. cDNA microarray analyses identified inhibitor of DNA binding (Id) proteins as BMP2 gene targets. I showed that Id2 and Id3 are required for BMP2 to stimulate Fshb transcription synergistically with activin A. Additionally, Id2 and Id3 physically interact with SMAD3, a major effector of activin signaling, to cooperatively stimulate Fshb transcription. Using gonadotrope cells, I showed that BMP2 signals via BMPRIA, BMPR2 and the intracellular signaling proteins SMADs 1 and 5 to stimulate Id3 transcription. I identified a novel BMP2 response element (BRE) in the proximal murine Id3 promoter that mediates SMAD1/5-dependent Id3 transcription. Furthermore, this BRE acts cooperatively with a previously identified distal BRE to mediate BMP2-stimulated Id3 expression. Overall, my work defines a mechanism whereby BMP2 regulates Fshb expression synergistically with activin A. By understanding multiple pathways mediating Fshb expression, we will develop a more complete picture of fundamental mechanisms governing reproductive physiology in mammals. Such knowledge may provide the necessary foundation for novel insights into causes of some forms of infertility and may therefore lead to the development of newer and more effective treatments.

ISBN: 9780494745274Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Bone morphogenetic protein 2 (BMP2) regulates follicle-stimulating hormone beta subunit (Fshb) expression in gonadotrope cells.
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245 1 0 $a Bone morphogenetic protein 2 (BMP2) regulates follicle-stimulating hormone beta subunit (Fshb) expression in gonadotrope cells.
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520 $a Proper follicle-stimulating hormone (FSH) synthesis, secretion, and action are required for normal reproductive function in mammals. A major goal of our lab and of this thesis is to reveal the intracellular mechanisms controlling FSH synthesis. The expression of the Fshb subunit gene (Fshb) is rate-limiting in production of the mature dimeric hormone and is regulated by numerous endocrine hormones and paracrine acting factors, including gonadotropin-releasing hormone, sex steroids, and transforming growth factor beta (TGFbeta) superfamily ligands such as activins. Recent studies suggest that bone morphogenetic proteins (BMPs), a sub-family of TGFbeta family ligands, also regulate Fshb transcription. BMP2 and BMP4 were further observed to stimulate Fshb transcription synergistically with activins. Here, I used the immortalized murine gonadotrope cell line, LbetaT2, to investigate mechanisms by which BMP2 regulates Fshb gene expression. I determined that BMP2 acts through the BMP receptors BMPR1A and BMPR2 to stimulate Fshb transcription. The data suggest that BMP2's effect on Fshb expression is more significant when acting synergistically with activins, and appears to depend on BMP-stimulated gene expression. cDNA microarray analyses identified inhibitor of DNA binding (Id) proteins as BMP2 gene targets. I showed that Id2 and Id3 are required for BMP2 to stimulate Fshb transcription synergistically with activin A. Additionally, Id2 and Id3 physically interact with SMAD3, a major effector of activin signaling, to cooperatively stimulate Fshb transcription. Using gonadotrope cells, I showed that BMP2 signals via BMPRIA, BMPR2 and the intracellular signaling proteins SMADs 1 and 5 to stimulate Id3 transcription. I identified a novel BMP2 response element (BRE) in the proximal murine Id3 promoter that mediates SMAD1/5-dependent Id3 transcription. Furthermore, this BRE acts cooperatively with a previously identified distal BRE to mediate BMP2-stimulated Id3 expression. Overall, my work defines a mechanism whereby BMP2 regulates Fshb expression synergistically with activin A. By understanding multiple pathways mediating Fshb expression, we will develop a more complete picture of fundamental mechanisms governing reproductive physiology in mammals. Such knowledge may provide the necessary foundation for novel insights into causes of some forms of infertility and may therefore lead to the development of newer and more effective treatments.
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