Smad7 enables STAT3 activation and promotes pluripotency independent of TGF-β signaling

Yu, Yi; Gu, Shuchen; Li, Wenjian; Sun, Chuang; Chen, Fenfang; Xiao, Mu; Wang, Lei; Xu, Dewei; Li, Ye; Ding, Chen; Xia, Zongping; Li, Yang; Ye, Sheng; Xu, Pinglong; Zhao, Bin; Qin, Jun; Chen, Ye-Guang; Lin, Xia; Feng, Xin‐Hua

doi:10.1073/pnas.1705755114

Cited by 52 publications

(43 citation statements)

References 54 publications

(48 reference statements)

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“…Considering REGγ knockout mice can survive and breed normally, we assume that targeting REGγ may be an alternative option for ATC therapy in the future with less side effects than inhibition of the conventional ubiquitin-proteasome degradation system. In addition, Smad7 has TGF-β-independent function in promoting pluripotency by amplifying STAT3 activation [34]. Thus, our study suggests: (1) targeting Smad7 downstream of TGF-β but not directly affecting receptor levels, may be an economical approach.…”

Section: Discussionmentioning

confidence: 80%

REGγ ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-β pathway

Jiao

Zhang

et al. 2019

Cell Death Differ

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Anaplastic thyroid cancer (ATC) is the most aggressive human thyroid malignancy, characterized by dedifferentiation and resistance to radioiodine therapy. The underlying mechanisms regulating ATC dedifferentiation are largely unknown. Here, we show that REGγ, a noncanonical proteasome activator highly expressed in ATC, is an important regulator of differentiation in ATC cells. Ablation of REGγ significantly restored expression of thyroid-specific genes, enhanced iodine uptake, and improved the efficacy of 131 I therapy in ATC xenograft models. Mechanistically, REGγ directly binds to the TGF-β signaling antagonist Smad7 and promotes its degradation, leading to the activation of the TGF-β signal pathway. With gain-and loss-of-function studies, we demonstrate that Smad7 is an important mediator for the REGγ function in ATC cell dedifferentiation, which is supported by expression profiles in human ATC tissues. It seems that REGγ impinges on repression of thyroid-specific genes and promotion of tumor malignancy in ATC cells by activating the TGF-β signal pathway via degradation of Smad7. Thus, REGγ may serve as a novel therapeutic target for allowing radioiodine therapy in anaplastic thyroid cancer patients with poor prognosis.

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Section: Discussionmentioning

confidence: 80%

REGγ ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-β pathway

Jiao

Zhang

et al. 2019

Cell Death Differ

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“…Obesity and older age are high-risk factors for developing diabetes [ 1 ], and over-production of TGF-β in the hypothalamic POMC neurons promotes glucose disorders under these conditions [ 8 ]. As an inhibitor of TGF-β signaling [ 16 ], the role of central Smad7 in glucose metabolism has not been investigated, although many functions of Smad7 in peripheral tissues have been reported [ 12 ]. Based on the well-known relationship between TGF-β and Smad7 [ 16 ], we speculated that hypothalamic Smad7 expression levels might be high in response to the over-production of TGF-β in HFD-fed or middle-aged mice.…”

Section: Discussionmentioning

confidence: 99%

“…Once activated, Smad7 binds to TGF-β type 1 receptor (TβR1) and recruits ubiquitin ligase to degrade TβR1 or protein phosphatase 1c (PP1c) to dephosphorylate TβR1 [ 10 , 11 ]. In addition to the TGF-β-dependent regulatory mechanism, Smad7 may also regulate downstream signaling independent of TGF-β [ 12 ]. Smad7 has been shown to affect the regulation of many processes (i.e., via intensifying enteritis, promoting tumor cell growth, and inhibiting hepatic fibrosis) [ [13] , [14] , [15] ].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Smad7 in hypothalamic POMC neurons disrupts glucose balance by attenuating central insulin signaling

Yuan

Yin

Deng

et al. 2020

Molecular Metabolism

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Objective Although the hypothalamus is crucial for peripheral metabolism control, the signals in specific neurons involved remain poorly understood. The aim of our current study was to explore the role of the hypothalamic gene mothers against decapentaplegic homolog 7 (Smad7) in peripheral glucose disorders. Methods We studied glucose metabolism in high-fat diet (HFD)-fed mice and middle-aged mice with Cre-mediated recombination causing 1) overexpression of Smad7 in hypothalamic proopiomelanocortin (POMC) neurons, 2) deletion of Smad7 in POMC neurons, and 3) overexpression of protein kinase B (AKT) in arcuate nucleus (ARC) in Smad7 overexpressed mice. Intracerebroventricular (ICV) cannulation of insulin was used to test the hypothalamic insulin sensitivity in the mice. Hypothalamic primary neurons were used to investigate the mechanism of Smad7 regulating hypothalamic insulin signaling. Results We found that Smad7 expression was increased in POMC neurons in the hypothalamic ARC of HFD-fed or middle-aged mice. Furthermore, overexpression of Smad7 in POMC neurons disrupted the glucose balance, and deletion of Smad7 in POMC neurons prevented diet- or age-induced glucose disorders, which was likely to be independent of changes in body weight or food intake. Moreover, the effect of Smad7 was reversed by overexpression of AKT in the ARC. Finally, Smad7 decreased AKT phosphorylation by activating protein phosphatase 1c in hypothalamic primary neurons. Conclusions Our results demonstrated that an excess of central Smad7 in POMC neurons disrupts glucose balance by attenuating hypothalamic insulin signaling. In addition, we found that this regulation was mediated by the activity of protein phosphatase 1c.

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“…In early-stage BL, the expression levels of SOX2, OCT4, and NANOG were not signi cantly different according to SOX2 targeting ( Figure 4A). The expression of SOX17 decreased, and the expression of SMAD7, which is known to be involved in ES cell self-renewal and iPSC reprogramming, also decreased (25). KDM8 is directly controlled by SOX2, which is known to regulate embryonic cell proliferation, and its expression is decreased in SOX2-targeted blastocyst ( Figure 3C) (26,27).…”

Section: Effects Of Sox2-targeting Plasmid Microinjection On Embryo Dmentioning

confidence: 98%

Identification of the Role of SOX2 During Early Embryogenesis in Pigs

Lee¹,

Oh²,

Kim³

et al. 2020

Preprint

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BackgroundThe lineage specification of mammalian embryos during preimplantation development has been studied for a long time but is still unclear. To understand the developmental process, many studies have examined lineage markers and mechanisms focusing on mouse embryos, but there are differences from human embryos. Pigs have been studied extensively in the field of disease model animals and xenotransplantation because of their physiological similarity with humans. Therefore, it is necessary to analyze gene expression patterns and lineage specification markers during early embryogenesis in pigs, a model animal similar to humans.ResultsAnalysis of the expression pattern of the core pluripotent factors (OCT4, SOX2 and NANOG) of preimplantation porcine embryos showed that SOX2 was only expressed in some cells from the early stage, so SOX2 was selected as an ICM inducible factor candidate. Next, transcript and protein expression patterns were estimated at the early stage (Day 5) and late stage (Day 7) of blastocysts injected with the CRISPR Cas9 system selected through gRNA validation. An ICC assay revealed that the expression of ICM-related genes (SOX2, NANOG and SOX17), except OCT4, was suppressed, and the total cell number was also decreased. Likewise, according to real-time PCR analysis, pluripotency-related genes (NANOG, SOX17 and SMAD7), excluding OCT4, and proliferation-related genes (KDM8 and DDB1) were decreased in SOX2-targeted blastocysts, which showed more differences in late-stage blastocyst than in early-stage blastocyst. Last, in SOX2-overexpressing embryos, the total blastocyst cell number was greatly increased, but the ICM/TE ratio decreased.ConclusionsTaken together, our results demonstrated SOX2 is essential for ICM formation and cell proliferation in porcine early stage embryogenesis. These findings will help to elucidate gene regulation related to lineage specification during porcine early development.

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Smad7 enables STAT3 activation and promotes pluripotency independent of TGF-β signaling

Cited by 52 publications

References 54 publications

REGγ ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-β pathway

REGγ ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-β pathway

Overexpression of Smad7 in hypothalamic POMC neurons disrupts glucose balance by attenuating central insulin signaling

Identification of the Role of SOX2 During Early Embryogenesis in Pigs

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