SMAD3 Activation: A Converging Point of Dysregulated TGF-Beta Superfamily Signaling and Genetic Aberrations in Granulosa Cell Tumor Development?

Fang, Xin; Gao, Yang; Li, Qinglei

doi:10.1095/biolreprod.116.143412

Cited by 17 publications

(22 citation statements)

References 90 publications

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“…These ligands bind to their membrane receptors and trigger the serine/threonine protein kinase activity of type 2 receptor (TGFBR2) and type 1 receptor (TGFBR1), and then the activated receptor phosphorylates intracellular SMAD2 (Sma- and Mad-related protein 2) and SMAD3. Subsequently, phosphorylated SMAD2 and SMAD3 form a heteromeric complex with SMAD4 (co-SMAD, the central signaling component of the TGF-β superfamily) 27,28 . Ultimately, the complex translocates into the nucleus and regulates gene expression by binding to the target gene promoter region, termed an SMAD-binding element (SBE), and recruiting distinct transcription factors 29 .…”

Section: Introductionmentioning

confidence: 99%

Transforming growth factor-β is involved in maintaining oocyte meiotic arrest by promoting natriuretic peptide type C expression in mouse granulosa cells

Yang

et al. 2019

Cell Death Dis

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Natriuretic peptide type C (NPPC) secreted by mural granulosa cells (MGCs) maintains oocyte meiotic arrest via the activation of guanylyl cyclase-linked natriuretic peptide receptor 2 (NPR2). Here, we investigated the effect of transforming growth factor (TGF)-β on NPPC expression in MGCs and oocyte maturation. TGF-β ligands (TGFB1 and TGFB3, but not TGFB2) and receptors (TGFBR1 and TGFBR2) were predominantly expressed in MGCs. The activation of the follicle-stimulating hormone (FSH) receptor by FSH/equine chorionic gonadotropin (eCG) increased the levels of TGFB1, TGFBR2, and TGF-β downstream SMAD proteins in MGCs, which were decreased following the activation of the luteinizing hormone (LH) receptor by human chorionic gonadotropin (hCG). TGF-β significantly increased the gene and protein levels of NPPC in cultured MGCs through SMAD3 binding to Nppc promoter regions. In the presence of FSH, TGF-β further increased NPPC levels and inhibited oocyte meiotic resumption of cumulus-oocyte complexes (COCs). Moreover, Tgfbr2 -specific depletion in granulosa cells using Fshr-Cre mice reduced NPPC mRNA and protein levels, resulting in the weak maintenance of oocyte meiotic arrest within large antral follicles. Tgfbr2 depletion also impaired follicle development, ovulation, and female fertility. Taken together, TGF-β-promoted NPPC in MGCs is involved in maintaining oocyte meiotic arrest. FSH and LH could regulate NPPC levels in MGCs via TGF-β and then control the process of oocyte meiosis.

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Section: Introductionmentioning

confidence: 99%

Transforming growth factor-β is involved in maintaining oocyte meiotic arrest by promoting natriuretic peptide type C expression in mouse granulosa cells

Yang

et al. 2019

Cell Death Dis

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“…More recent studies have revealed that histone lysine demethylases such as KDM3A play important roles in renal cell carcinoma, the most common kidney cancer, via hypoxia-mediated angiogenesis pathways ( 77–79 ). Smad3 is an intracellular signal transducer and transcriptional modulator activated by transforming growth factor (TGF)-β ( 80 ). On the molecular level, TGF-β/Smad3 signaling pathway plays a central role in fibrotic kidney disease ( 81 ).…”

Section: Discussionmentioning

confidence: 99%

Role for first zinc finger of WT1 in DNA sequence specificity: Denys–Drash syndrome-associated WT1 mutant in ZF1 enhances affinity for a subset of WT1 binding sites

Wang

Horton

Zheng³

et al. 2017

Nucleic Acids Research

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Wilms tumor protein (WT1) is a Cys2-His2 zinc-finger transcription factor vital for embryonic development of the genitourinary system. The protein contains a C-terminal DNA binding domain with four tandem zinc-fingers (ZF1–4). An alternative splicing of Wt1 can add three additional amino acids—lysine (K), threonine (T) and serine (S)—between ZF3 and ZF4. In the −KTS isoform, ZF2–4 determine the sequence-specificity of DNA binding, whereas the function of ZF1 remains elusive. Three X-ray structures are described here for wild-type −KTS isoform ZF1–4 in complex with its cognate DNA sequence. We observed four unique ZF1 conformations. First, like ZF2–4, ZF1 can be positioned continuously in the DNA major groove forming a ‘near-cognate’ complex. Second, while ZF2–4 make base-specific interactions with one DNA molecule, ZF1 can interact with a second DNA molecule (or, presumably, two regions of the same DNA molecule). Third, ZF1 can intercalate at the joint of two tail-to-head DNA molecules. If such intercalation occurs on a continuous DNA molecule, it would kink the DNA at the ZF1 binding site. Fourth, two ZF1 units can dimerize. Furthermore, we examined a Denys–Drash syndrome-associated ZF1 mutation (methionine at position 342 is replaced by arginine). This mutation enhances WT1 affinity for a guanine base. X-ray crystallography of the mutant in complex with its preferred sequence revealed the interactions responsible for this affinity change. These results provide insight into the mechanisms of action of WT1, and clarify the fact that ZF1 plays a role in determining sequence specificity of this critical transcription factor.

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“…A causal link between the mRNA expression levels of TGFBR1 and the development of GCTs in humans has not been established [ 43 ]. Growing evidence supports that activation of TGFB/activin signaling may represent a driving force of GCT development in mice [ 44 ]. It has also been found that TGFB/activin signaling is active in human GCTs [ 32 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

Disruption of postnatal folliculogenesis and development of ovarian tumor in a mouse model with aberrant transforming growth factor beta signaling

Gao

Fang

Vincent

et al. 2017

Reprod Biol Endocrinol

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BackgroundTransforming growth factor beta (TGFB) superfamily signaling is implicated in the development of sex cord-stromal tumors, a category of poorly defined gonadal tumors. The aim of this study was to determine potential effects of dysregulated TGFB signaling in the ovary using Cre recombinase driven by growth differentiation factor 9 (Gdf9) promoter known to be expressed in oocytes.MethodsA mouse model containing constitutively active TGFBR1 (TGFBR1CA) using Gdf9-iCre (termed TGFBR1-CAG9Cre) was generated. Hematoxylin and eosin (H & E) staining, follicle counting, and immunohistochemistry and immunofluorescence analyses using antibodies directed to Ki67, forkhead box L2 (FOXL2), forkhead box O1 (FOXO1), inhibin alpha (INHA), and SRY (sex determining region Y)-box 9 were performed to determine the characteristics of the TGFBR1-CAG9Cre ovary. Terminal deoxynucleotidyl transferase (TdT) labeling of 3’-OH ends of DNA fragments, real-time PCR, and western blotting were used to examine apoptosis, select gene expression, and TGFBR1 activation. RNAscope in situ hybridization was used to localize the expression of GLI-Kruppel family member GLI1 (Gli1) in ovarian tumor tissues.ResultsTGFBR1-CAG9Cre females were sterile. Sustained activation of TGFBR1 led to altered granulosa cell proliferation evidenced by high expression of Ki67. At an early age, these mice demonstrated follicular defects and development of ovarian granulosa cell tumors, which were immunoreactive for granulosa cell markers including FOXL2, FOXO1, and INHA. Further histochemical and molecular analyses provided evidence of overactivation of TGFBR1 in the granulosa cell compartment during ovarian pathogenesis in TGFBR1-CAG9Cre mice, along with upregulation of Gli1 and Gli2 and downregulation of Tgfbr3 in ovarian tumor tissues.ConclusionsThese results reinforce the role of constitutively active TGFBR1 in promoting ovarian tumorigenesis in mice. The mouse model created in this study may be further exploited to define the cellular and molecular mechanisms of TGFB/activin downstream signaling in granulosa cell tumor development. Future studies are needed to test whether activation of TGFB/activin signaling contributes to the development of human granulosa cell tumors.Electronic supplementary materialThe online version of this article (10.1186/s12958-017-0312-z) contains supplementary material, which is available to authorized users.

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SMAD3 Activation: A Converging Point of Dysregulated TGF-Beta Superfamily Signaling and Genetic Aberrations in Granulosa Cell Tumor Development?

Cited by 17 publications

References 90 publications

Transforming growth factor-β is involved in maintaining oocyte meiotic arrest by promoting natriuretic peptide type C expression in mouse granulosa cells

Transforming growth factor-β is involved in maintaining oocyte meiotic arrest by promoting natriuretic peptide type C expression in mouse granulosa cells

Role for first zinc finger of WT1 in DNA sequence specificity: Denys–Drash syndrome-associated WT1 mutant in ZF1 enhances affinity for a subset of WT1 binding sites

Disruption of postnatal folliculogenesis and development of ovarian tumor in a mouse model with aberrant transforming growth factor beta signaling

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