Salt-inducible kinases (SIKs) regulate TGFβ-mediated transcriptional and apoptotic responses
Luke D. HutchinsonNicola J. DarlingStephanos NicolaouIlaria GoriDaniel R. SquairPhilip CohenCaroline S. HillGopal P. Sapkota
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Abstract The signalling pathways initiated by members of the transforming growth factor-β (TGFβ) family of cytokines control many metazoan cellular processes, including proliferation and differentiation, epithelial–mesenchymal transition (EMT) and apoptosis. TGFβ signalling is therefore strictly regulated to ensure appropriate context-dependent physiological responses. In an attempt to identify novel regulatory components of the TGFβ signalling pathway, we performed a pharmacological screen by using a cell line engineered to report the endogenous transcription of the TGFβ-responsive target gene PAI-1 . The screen revealed that small molecule inhibitors of salt-inducible kinases (SIKs) attenuate TGFβ-mediated transcription of PAI-1 without affecting receptor-mediated SMAD phosphorylation, SMAD complex formation or nuclear translocation. We provide evidence that genetic inactivation of SIK isoforms also attenuates TGFβ-dependent transcriptional responses. Pharmacological inhibition of SIKs by using multiple small-molecule inhibitors potentiated apoptotic cell death induced by TGFβ stimulation. Our data therefore provide evidence for a novel function of SIKs in modulating TGFβ-mediated transcriptional and cellular responses.Keywords:
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Porcine uterine tissues were collected from Days 10 to 14 of gestation (peri-implantation period) or corresponding days of the estrous cycle. Results indicated a marked increase in beta transforming growth factors (TGFβ1, TGFβ2, and TGFβ3) and TGFβ receptor (type I and type II) immunostaining in uterine luminal epithelium (ULE) between Days 10 and 14 of gestation, but there was no increase in ULE immunostaining on the corresponding days of the estrous cycle. Uterine glands and stroma were intensely immunopositive in pregnant gilts for TGFβ isoforms and their receptors, but immunostaining was weak to undetectable in cycling gilts. No differences were detected in myometrium, in which immunostaining was moderate in both cycling and pregnant gilts. Additionally, TGFβ2 and TGFβ receptor (type I and type II) immunostaining was detected in uterine monocyte/macrophage-like cells. Western blotting detected the presence of all three TGFβ isoforms in uterine luminal flushings. The CCL64 cell TGFβ bioassay detected bioactive TGFβs in uterine luminal flushings on Days 12, 13, and 14 of gestation. These results strongly indicate that uterine expression of TGFβs and their receptors is pregnancy specific and that bioactive TGFβs are present at the conceptus-maternal interface in the peri-implantation period in pigs. Thus TGFβs are likely to be involved in autocrine-paracrine interactions between the maternal uterus and the conceptus.
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Members of transforming growth factor-β(TGF β) superfamily play an important roles in regulating cell growth, differentiation and tissue homeostasis. Smad proteins possess special structure and property and play important roles in transforming growth factor-β(TGF-β) signal transduction pathway. TGF-β activates the downstream Smad proteins,which initiate intracellular signaling pathways via its interaction with TGF-β receptor(TGF-βR) . Research on the varieties,structures and function of Smad proteins,and the complicated regulating mechanism of Smad proteins in TGF-β superfamily signaling transduction are very significative.
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Transforming growth factor-β; Smad; Signal transduction
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Aims: Latent transforming growth factor (TGF)-β binding proteins (LTBPs) play important roles in the secretion and activation of TGF-β, which is a key factor in wound healing and fibrosis. TGF-β is synthesized as latent high-molecular weight complex, composed of TGF-β, a part of the TGF-β precursor, and the latent TGF-β binding protein. LTBP for itself is an ingredient of the extracellular matrix, targets TGF-β thither, and participates in the activation of free TGF-β. We have previously shown that mice lacking LTBP–1 are less prone to hepatic fibrogenesis [1]. To understand the underlying mechanisms, we here examined the capability of embryonic cells from wildtype and LTBP–1 knockout mice to secrete active TGF-β.
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The transforming growth factor-β(TGF-β)/smad signaling pathway has an important role in carcinogenesis.In recent years,many investigations have revealed that TGF-β super-family ligands,receptors,smads protein,up stream and down stream regulators and cross-talk among many signaling pathways function in the correlative cancer.This review attempts to state transforming growth factor-β/smad signaling pathway and factor-β1、smad4 in cervical carcinoma.
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This article refers to:Cripto Binds Transforming Growth Factor β (TGF-β) and Inhibits TGF-β Signaling
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As a crucial regulatory molecule in the context of vascular stenosis, transforming growth factor-β (TGF-β), plays a pivotal role in its initiation and progression. TGF-β, a member of the TGF-β superfamily, can bind to the TGF-β receptor and transduce extracellular to intracellular signals through canonical Smad dependent or noncanonical signaling pathways to regulate cell growth, proliferation, differentiation, and apoptosis. Restenosis remains one of the most challenging problems in cardiac, cerebral, and peripheral vascular disease worldwide. The mechanisms for occurrence and development of restenosis are diverse and complex. The TGF-β pathway exhibits diversity across various cell types. Hence, clarifying the specific roles of TGF-β within different cell types and its precise impact on vascular stenosis provides strategies for future research in the field of stenosis.
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