Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling

Nakao, Akihiro; Afrakhte, Mozhgan; Morn, Anita; Nakayama, Takuya; Christian, Jan L.; Heuchel, Rainer; Itoh, Susumu; Kawabata, Masahiro; Heldin, Nils‐Erik; Heldin, Carl‐Henrik; Dijke, Peter ten

doi:10.1038/39369

Cited by 1,702 publications

(1,010 citation statements)

References 29 publications

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“…5 and Supplementary Table S4). In general, SMAD6 and SMAD7 play negative feedback loop in the TGF-β/SMAD signaling pathway and are considered as potential regulators of ovarian function (Nakao et al 1997, Uchida et al 2000, Tsukamoto et al 2014, Li 2015, while SMAD9 suppresses intracellular bone morphogenetic protein (BMP) signaling (Tsukamoto et al 2014). By decreasing the levels of these inhibitory SMADs, SMAD4-silencing might reduce inhibitory SMAD-related pathways or ovarian function in porcine follicular GCs.…”

Section: Discussionmentioning

confidence: 99%

A comprehensive transcriptomic view on the role of SMAD4 gene by RNAi-mediated knockdown in porcine follicular granulosa cells

Zhang¹,

Du²,

Wei³

et al. 2016

Reproduction

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As a key mediator of the transforming growth factor-beta (TGF-β) signaling pathway, which plays a pivotal role in regulating mammalian reproductive performance, Sma-and Mad-related protein 4 (SMAD4) is closely associated with the development of ovarian follicular. However, current knowledge of the genome-wide view on the role of SMAD4 gene in mammalian follicular granulosa cells (GCs) is still largely unknown. In the present study, RNA-Seq was performed to investigate the effects of SMAD4 knockdown by RNA interference (SMAD4-siRNA) in porcine follicular GCs. A total of 1025 differentially expressed genes (DEGs), including 530 upregulated genes and 495 downregulated genes, were identified in SMAD4-siRNA treated GCs compared with that treated with NC-siRNA. Furthermore, functional enrichment analysis indicated that upregulated DEGs in SMAD4-siRNA treated cells were mainly enriched in cell-cycle related processes, interferon signaling pathway, and immune system process, while downregulated DEGs in SMAD4-siRNA treated cells were mainly involved in extracellular matrix organization/disassembly, pathogenesis, and cell adhesion. In particular, cell cycle and TGF-β signaling pathway were discovered as the canonical pathways changed under SMAD4-silencing. Taken together, our data reveals SMAD4 knockdown alters the expression of numerous genes involved in key biological processes of the development of follicular GCs and provides a novel global clue of the role of SMAD4 gene in porcine follicular GCs, thus improving our understanding of regulatory mechanisms of SMAD4 gene in follicular development.Reproduction (2016) 152 81-89

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Section: Discussionmentioning

confidence: 99%

A comprehensive transcriptomic view on the role of SMAD4 gene by RNAi-mediated knockdown in porcine follicular granulosa cells

Zhang¹,

Du²,

Wei³

et al. 2016

Reproduction

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“…Once formed the complexes, the SMADs translocate in the nucleus where they regulate target genes (Attisano & Wrana 2000). In contrast, the inhibitory SMAD (I-SMAD), SMAD7, binds to TbRI and prevents the phosphorylation of R-SMADs, resulting in the inhibition of TGFb signaling (Imamura et al 1997, Nakao et al 1997. A SMAD ubiquitin regulatory factor 1 (SMURF1), being a HECTtype E3 ubiquitin ligase, interacts with I-SMAD7 and enhances the turnover of TbRI (Suzuki et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Role of reduced expression of SMAD4 in papillary thyroid carcinoma

D’Inzeo¹,

Nicolussi²,

A³

et al. 2010

Journal of Molecular Endocrinology

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It has been demonstrated that transforming growth factor-b (TGFb) and other members of TGFb superfamily play an important role in thyroid proliferative diseases. The deficiencies of SMAD4 are responsible to accelerate the malignant progression of neoplastic lesions in several types of tumors. Therefore, the objective of the present study was to determine the functional role of reduced expression of SMAD4 in human papillary thyroid carcinogenesis. For this purpose, we examined the TGFb response in two cell lines, TPC-1 and BCPAP. Our data demonstrated for the first time that these cells showed a strong reduction in the level of SMAD4 protein, which was responsible for an alteration of TGFb signaling and for some of the TGFb-mediated biological effects. The overexpression of SMAD4, restoring TGFb transduction, determined a significant increase of antiproliferative response to TGFb, and reduced the invasive behavior of these cells. Therefore, our data indicated that reduction of SMAD4 may play a significant role in thyroid carcinogenesis.

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“…SMAD7 is an inhibitory SMAD that antagonizes TGFb and BMP signaling in vitro (Nakao et al 1997, Yanagisawa et al 2001. SMAD7 is functionally distinct from SMAD6 (Yan et al 2009, Yan & Chen 2011.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that SMAD6 preferentially inhibits BMP signaling (Hata et al 1998, Ishisaki et al 1999, whereas SMAD7 is capable of targeting TGFb or both TGFb and BMP pathways (Nakao et al 1997, Souchelnytskyi et al 1998, Ishisaki et al 1999. The functions of inhibitory SMADs are being revealed by knockout mouse models.…”

Section: Introductionmentioning

confidence: 99%

SMAD7 antagonizes key TGFβ superfamily signaling in mouse granulosa cells in vitro

Gao¹,

Wen²,

Wang³

et al. 2013

Reproduction

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Transforming growth factor b (TGFb) superfamily signaling is essential for female reproduction. Dysregulation of the TGFb signaling pathway can cause reproductive diseases. SMA and MAD (mothers against decapentaplegic) (SMAD) proteins are downstream signaling transducers of the TGFb superfamily. SMAD7 is an inhibitory SMAD that regulates TGFb signaling in vitro. However, the function of SMAD7 in the ovary remains poorly defined. To determine the signaling preference and potential role of SMAD7 in the ovary, we herein examined the expression, regulation, and function of SMAD7 in mouse granulosa cells. We showed that SMAD7 was expressed in granulosa cells and subject to regulation by intraovarian growth factors from the TGFb superfamily. TGFB1 (TGFb1), bone morphogenetic protein 4, and oocyte-derived growth differentiation factor 9 (GDF9) were capable of inducing Smad7 expression, suggesting a modulatory role of SMAD7 in a negative feedback loop. Using a small interfering RNA approach, we further demonstrated that SMAD7 was a negative regulator of TGFB1. Moreover, we revealed a link between SMAD7 and GDF9-mediated oocyte paracrine signaling, an essential component of oocyte-granulosa cell communication and folliculogenesis. Collectively, our results suggest that SMAD7 may function during follicular development via preferentially antagonizing and/or fine-tuning essential TGFb superfamily signaling, which is involved in the regulation of oocyte-somatic cell interaction and granulosa cell function.

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Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling

Cited by 1,702 publications

References 29 publications

A comprehensive transcriptomic view on the role of SMAD4 gene by RNAi-mediated knockdown in porcine follicular granulosa cells

A comprehensive transcriptomic view on the role of SMAD4 gene by RNAi-mediated knockdown in porcine follicular granulosa cells

Role of reduced expression of SMAD4 in papillary thyroid carcinoma

SMAD7 antagonizes key TGFβ superfamily signaling in mouse granulosa cells in vitro

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