A Smad3 and TTF-1/NKX2-1 complex regulates Smad4-independent gene expression

Isogaya, Kazunobu; Koinuma, Daizo; Tsutsumi, Sadami; Saito, Roy-Akira; Miyazawa, Keiji; Aburatani, Hiroyuki; Miyazono, Kohei

doi:10.1038/cr.2014.97

Cited by 49 publications

(57 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RNA‐seq was performed as described previously (Isogaya et al ., 2014; Mizutani et al ., 2016). cDNA libraries were prepared using the RNeasy Mini Kit with the On‐Column DNase Digestion Set (QIAGEN, Venlo, The Netherlands), Dynabeads mRNA DIRECT Purification Kit, and the Ion Total RNA‐Seq Kit v2 (Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

ZEB1‐regulated inflammatory phenotype in breast cancer cells

et al. 2017

Self Cite

View full text Add to dashboard Cite

Zinc finger E‐box binding protein 1 (ZEB1) and ZEB2 induce epithelial‐mesenchymal transition (EMT) and enhance cancer progression. However, the global view of transcriptional regulation by ZEB1 and ZEB2 is yet to be elucidated. Here, we identified a ZEB1‐regulated inflammatory phenotype in breast cancer cells using chromatin immunoprecipitation sequencing and RNA sequencing, followed by gene set enrichment analysis (GSEA) of ZEB1‐bound genes. Knockdown of ZEB1 and/or ZEB2 resulted in the downregulation of genes encoding inflammatory cytokines related to poor prognosis in patients with cancer, including IL6 and IL8, therefore suggesting that ZEB1 and ZEB2 have similar functions in terms of the regulation of production of inflammatory cytokines. Antibody array and ELISA experiments confirmed that ZEB1 controlled the production of the IL‐6 and IL‐8 proteins. The secretory proteins regulated by ZEB1 enhanced breast cancer cell proliferation and tumor growth. ZEB1 expression in breast cancer cells also affected the growth of fibroblasts in cell culture, and the accumulation of myeloid‐derived suppressor cells in tumors in vivo. These findings provide insight into the role of ZEB1 in the progression of cancer, mediated by inflammatory cytokines, along with the initiation of EMT.

show abstract

Section: Methodsmentioning

confidence: 99%

ZEB1‐regulated inflammatory phenotype in breast cancer cells

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Further investigation revealed that NKX2-1 disrupts the Smad3-Smad4 complex in the nucleus and dramatically alters both the binding strength and distribution of Smad3 throughout the genome (Fig. 3A) [126]. In addition, NKX2-1 forms a complex with Smad3, but without Smad4, and the Smad3-NKX2-1 complex regulates the expression of target genes related to other processes of cancer, such as LMO3 [126].…”

Section: Tgf-β-induced Target Gene Expression and Emt In Lung Adenocamentioning

confidence: 99%

Intracellular and extracellular TGF-β signaling in cancer: some recent topics

et al. 2018

Self Cite

View full text Add to dashboard Cite

Transforming growth factor (TGF)-β regulates a wide variety of cellular responses, including cell growth arrest, apoptosis, cell differentiation, motility, invasion, extracellular matrix production, tissue fibrosis, angiogenesis, and immune function. Although tumor-suppressive roles of TGF-β have been extensively studied and well-characterized in many cancers, especially at early stages, accumulating evidence has revealed the critical roles of TGF-β as a pro-tumorigenic factor in various types of cancer. This review will focus on recent findings regarding epithelial-mesenchymal transition (EMT) induced by TGF-β, in relation to crosstalk with some other signaling pathways, and the roles of TGF-β in lung and pancreatic cancers, in which TGF-β has been shown to be involved in cancer progression. Recent findings also strongly suggested that targeting TGF-β signaling using specific inhibitors may be useful for the treatment of some cancers. TGF-β plays a pivotal role in the differentiation and function of regulatory T cells (Tregs). TGF-β is produced as latent high molecular weight complexes, and the latent TGF-β complex expressed on the surface of Tregs contains glycoprotein A repetitions predominant (GARP, also known as leucine-rich repeat containing 32 or LRRC32). Inhibition of the TGF-β activities through regulation of the latent TGF-β complex activation will be discussed.

show abstract

“…Since prior studies had shown that a large proportion of Smad-binding sites are found outside of promoter-proximal regions at putative enhancer elements (Kennedy et al 2011;Morikawa et al 2011;Schlenner et al 2012;Gaunt et al 2013), we considered whether Smad proteins occupy distal SBEs at the DOCK4 locus. To this end, we analyzed available Smad3 ChIP-seq (chromatin immunoprecipitation [ChIP] combined with deep sequencing) data (GSE51509) obtained from TGF-b-stimulated A549 cells (Isogaya et al 2014) and found two significant Smad3 peaks in the first intron of DOCK4 at +45 kb and +125 kb (Fig. 1I).…”

Section: Tgf-b Potently Induces Expression Of Dock4 Via the Smad Pathwaymentioning

confidence: 99%

TGF-β/Smad signaling through DOCK4 facilitates lung adenocarcinoma metastasis

Tai

Jin

et al. 2015

Genes Dev.

View full text Add to dashboard Cite

The mechanisms by which TGF-b promotes lung adenocarcinoma (ADC) metastasis are largely unknown. Here, we report that in lung ADC cells, TGF-b potently induces expression of DOCK4, but not other DOCK family members, via the Smad pathway and that DOCK4 induction mediates TGF-b's prometastatic effects by enhancing tumor cell extravasation. TGF-b-induced DOCK4 stimulates lung ADC cell protrusion, motility, and invasion without affecting epithelial-to-mesenchymal transition. These processes, which are fundamental to tumor cell extravasation, are driven by DOCK4-mediated Rac1 activation, unveiling a novel link between TGF-b and Rac1. Thus, our findings uncover the atypical Rac1 activator DOCK4 as a key component of the TGF-b/Smad pathway that promotes lung ADC cell extravasation and metastasis.

show abstract

A Smad3 and TTF-1/NKX2-1 complex regulates Smad4-independent gene expression

Cited by 49 publications

References 41 publications

ZEB1‐regulated inflammatory phenotype in breast cancer cells

ZEB1‐regulated inflammatory phenotype in breast cancer cells

Intracellular and extracellular TGF-β signaling in cancer: some recent topics

TGF-β/Smad signaling through DOCK4 facilitates lung adenocarcinoma metastasis

Contact Info

Product

Resources

About