Cell-specificity of transforming growth factor-β response is dictated by receptor bioavailability

Suszko, Magdalena I.; Woodruff, Teresa K.

doi:10.1677/jme.1.01936

Cited by 21 publications

(24 citation statements)

References 26 publications

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“…We did not examine ALK6 here because an earlier report indicated that it was not expressed in LbT2 cells or adult mouse pituitary (Otsuka & Shimasaki 2002). However, more recent work shows that this receptor is in fact expressed (Suszko & Woodruff 2006), and we confirm this observation here. Given that ALK6 is more similar to ALK3 than ALK2, one would predict that it will not potentiate the BMP2 response.…”

Section: Discussionsupporting

confidence: 85%

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Bone morphogenetic protein 2 and activin A synergistically stimulate follicle-stimulating hormone β subunit transcription

Lee

Khivansara²,

Santos³

et al. 2007

Journal of Molecular Endocrinology

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Transforming growth factor b superfamily ligands regulate pituitary FSH production and secretion. The best-described examples are the activins and inhibins, which respectively stimulate and hinder Fshb subunit transcription in gonadotrope cells. More recently, members of the bone morphogenetic protein (BMP) sub-family were shown to regulate FSH production in a manner analogous to the activins. Here, we used the murine gonadotrope cell line, LbT2, to investigate mechanisms through which BMP2 regulates the Fshb gene. Although expressed at low levels in LbT2 cells, Bmp2 mRNA was readily detected in adult murine pituitary gland. Recombinant BMP2 stimulated Fshb promoter-reporter activity, although its effects were weaker than those of equimolar activin A or B. BMP4 stimulated transcription comparably with BMP2, but BMPs 6 and 7 were about tenfold less potent. Remarkably, BMP2 and activin A synergistically upregulated Fshb transcription and endogenous Fshb mRNA levels in LbT2 cells. Although functionally cooperative, the two ligands appeared to use distinct intracellular mechanisms to mediate their responses because neither ligand altered the timing or magnitude of the other's effects. Receptor overexpression analyses suggested that BMP2 may preferentially signal through complexes of the type II receptor, BMPR2, and the type I receptor, activin receptor like kinase (ALK2; Acvr1), to stimulate Fshb transcription. BMP2 rapidly activated the Smad1/5/8 intracellular signaling cascade and Smad8 overexpression potentiated BMP2's effects. In summary, BMPs regulate Fshb transcription in LbT2 cells and can amplify the already robust effects of the activins through a distinct signaling mechanism. Because BMP2 is expressed in the adult mouse pituitary, it may act as critical paracrine co-regulator of FSH synthesis by gonadotropes.

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Section: Discussionsupporting

confidence: 85%

“…7). One report indicated no expression of ALK6 in LbT2 cells or mouse pituitary (Otsuka & Shimasaki 2002), whereas more recent work (Suszko & Woodruff 2006) showed that it is expressed at low levels and our data are consistent with the latter report (Fig. 7).…”

Section: Bmp Receptors and Receptor-regulated Smads Are Expressed In supporting

confidence: 93%

Bone morphogenetic protein 2 and activin A synergistically stimulate follicle-stimulating hormone β subunit transcription

Lee

Khivansara²,

Santos³

et al. 2007

Journal of Molecular Endocrinology

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“…Regulation of a specific transduction pathway through the availability of ligands and receptors is an established concept. In this context, Suszko and Woodruff [29] have demonstrated that receptor bioavailability would dictate the specificity of TGF-β action in rat pituitary gonadotropic cells. Therefore, the effects of TGF-β1 would depend on the balance between ALK1 and ALK5 in Leydig cells.…”

Section: Discussionmentioning

confidence: 99%

TGF-.BETA.1 System in Leydig Cells. Part I: Effect of hCG and Progesterone

González

Rulli

et al. 2010

Journal of Reproduction and Development

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Abstract. Transforming growth factor beta 1 (TGF-β1) modulates male reproductive function. Genetically modified mice overexpressing α/β subunits of hCG (hCG+) show Leydig cell hyperplasia/hypertrophy at prepuberty that disappears as the mice approach adulthood. In this study we analyzed the gene expression of TGF-β1, its specific receptors, type II (TGF-βRII) and type I (activin receptor-like kinase 1 and 5: ALK1 and ALK5), and co-receptor endoglin (CD105) in purified Leydig cells from hCG+ and wild-type mice at 3 and 8 weeks of age and the occurrence of TGF-β1, ALK1 and ALK5 by immunohistochemistry. The expression of TGF-β1 was higher in hCG+ mice at both ages studied, and no changes were observed in TGF-βRII. ALK5 diminished with age in wild-type mice, whereas ALK1 decreased in hCG+ mice at 8 weeks of age. Endoglin expression showed a marked increase in 3-week-old hCG+ animals. In vitro incubation of Leydig cells from wild-type animals with hCG (10 IU/ml) increased TGF-β1 and ALK5 expression. Progesterone (10 -6 M) induced endoglin expression. These studies provide novel evidence for differential gene and protein expression of ALK1 and ALK5 at different ages and endoglin expression and hormonal, in purified Leydig cells. Key words: ALK, Endoglin (CD105), Leydig, Testis, TGF-beta 1 (J. Reprod. Dev. 56: [389][390][391][392][393][394][395] 2010) esticular function is under the control of a complex network of hormones, growth factors and cytokines [1], including the transforming growth factor β (TGF-β) family that involves three related peptides: TGF-β1, TGF-β2 and TGF-β3. They share homology with other members of the family, such as inhibins, activins, anti-Mullerian hormone (AMH) and bone morphogenetic proteins (BMPs) [2,3]. These molecules have a critical role in regulating cell cycle progression and differentiation in a broad range of tissues under normal and pathological conditions [2,4,5]. In the testis, TGF-β regulates a variety of cellular processes, comprising the secretory functions of Leydig and Sertoli cells, the organization of peritubular myoid cells, testis development and spermatogenesis [5][6][7].Several mechanisms are known to regulate the expression of TGF-β ligands and receptors [3], but their functions in the testis are not well established. Testosterone and FSH suppress the expression of TGF-β1 in cultured porcine Leydig and Sertoli cells, respectively [8], and hCG stimulates TGF-βRI and TGF-βRII expression in cultured porcine Leydig cells, whereas steroid hormones have no effect [9]. New genetically modified animal models have proven important in increasing our understanding of testicular pathologies associated with gonadotropin function.Transgenic male mice overexpressing α and β subunits of hCG (hCG+ mice) are infertile, and their reproductive organs show severe alterations, such as smaller testes, enlarged seminal vesicles and prostate and dilated vasa deferentia and urinary bladder [10].In addition, testicular steroidogenesis is enhanced despite a clear down-regulation of LH/hCG recep...

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“…BMP4 is proteolytically activated by furin (15); however, BMP ligands do not regulate furin expression in mouse pituitary gonadotrope cells that express both BMP type I and type II receptors (27). Although it has been demonstrated that TGF␤1 can regulate furin gene expression in rat synoviocytes (28), this ligand cannot regulate furin mRNA in mouse pituitary gonadotrope cells because L␤T2 cells lack endogenous TGF␤ type II receptor and therefore are not responsive to TGF␤ ligand (29). This selective auto-regulation of furin by activin suggests that furin plays an important role in regulation of hormone biosynthesis and secretion from pituitary gonadotrope cells.…”

Section: Discussionmentioning

confidence: 99%

An Activin/Furin Regulatory Loop Modulates the Processing and Secretion of Inhibin α- and βB-Subunit Dimers in Pituitary Gonadotrope Cells

Antenos

Zhu

Jetly

et al. 2008

Journal of Biological Chemistry

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Of all ligands of the transforming growth factor ␤ superfamily, inhibins and activins are a physiologically relevant pair that are functional antagonists of each other. Activin stimulates whereas inhibin blocks follicle-stimulating hormone biosynthesis and secretion from pituitary gonadotrope cells, and together, inhibin and activin control the pituitary gonadal axis essential for normal reproductive function. Sharing a similar ␤-subunit, the secretion of inhibin heterodimers (␣/␤) or activin homodimers (␤/␤) as mature bioactive ligands depends, in part, on the proteolytic processing of precursor proteins. A short loop regulatory pathway controlling precursor processing and dimer secretion was discovered. Activin stimulates endogenous inhibin ␣-and ␤ B -subunit mRNA, protein, and proteolytic processing. Simultaneously, activin stimulated the proconvertase furin through a Smad2/3-dependent process. The data provide a mechanism where the regulation of furin and inhibin subunits cooperates in an important positive short feedback loop. This regulatory loop augments the secretion of bioactive mature activin B, as well as inhibin B dimers, necessary for local folliclestimulating hormone ␤ regulation.

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Cell-specificity of transforming growth factor-β response is dictated by receptor bioavailability

Cited by 21 publications

References 26 publications

Bone morphogenetic protein 2 and activin A synergistically stimulate follicle-stimulating hormone β subunit transcription

Bone morphogenetic protein 2 and activin A synergistically stimulate follicle-stimulating hormone β subunit transcription

TGF-.BETA.1 System in Leydig Cells. Part I: Effect of hCG and Progesterone

An Activin/Furin Regulatory Loop Modulates the Processing and Secretion of Inhibin α- and βB-Subunit Dimers in Pituitary Gonadotrope Cells

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