TGF-β1 Inhibits NF-κB Activity through Induction of IκB-α Expression in Human Salivary Gland Cells: A Possible Mechanism of Growth Suppression by TGF-β1

Azuma, Masayuki; Motegi, Katsumi; Aota, Keiko; Yamashita, Tsuyoshi; Yoshida, Hideo; Sato, Mitsunobu

doi:10.1006/excr.1999.4503

Cited by 58 publications

(41 citation statements)

References 51 publications

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“…Once IB␣ is phosphorylated or degraded, p50/p65 subunits become activated and translocate into the nucleus to activate the target genes. TGF-␤ is able to induce IB␣ expression (44); however, its intracellular mechanism remains unclear. In our study, we demonstrated that Smad7 was able to induce directly the ex- (Figures 4 through 6).…”

Section: Discussionmentioning

confidence: 99%

Signaling Mechanism of TGF-β1 in Prevention of Renal Inflammation

Wang¹,

Huang²,

Li³

et al. 2005

Journal of the American Society of Nephrology

230

231

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TGF-␤ has been shown to play a critical role in anti-inflammation; however, the signaling mechanisms of TGF-␤ in anti-inflammatory response remains largely unclear. This study reported that mice that overexpress latent TGF-␤1 on skin are protected against renal inflammation in a model of obstructive kidney disease and investigated the signaling mechanism of TGF-␤1 in inhibition of renal inflammation in vivo and in vitro. Seven days after urinary obstruction, wild-type mice developed severe renal inflammation, including massive T cell and macrophage infiltration and marked upregulation of IL-1␤, TNF-␣, and intercellular adhesion molecule-1 (all P < 0.001). Surprising, renal inflammation was prevented in transgenic mice. This was associated with an increase in latent TGF-␤1 in circulation (a 10-fold increase) and renal tissues (a 2.5-fold increase). Further studies showed that inhibition of renal inflammation in TGF-␤1 transgenic mice was also associated with a marked upregulation of renal Smad7 and IB␣ and a suppression of NF-B activation in the diseased kidney (all P < 0.01). These in vivo findings suggested the importance of TGF-␤-NF-B cross-talk signaling pathway in regulating renal inflammation. This was tested in vitro in a doxycycline-regulated Smad7-expressing renal tubular cell line. Overexpression of Smad7 was able to upregulate IB␣ directly in a time-and dose-dependent manner, thereby inhibiting NF-B activation and NF-B-driven inflammatory response. In conclusion, latent TGF-␤ may have protective roles in renal inflammation. Smad7-mediated inhibition of NF-B activation via the induction of IkB␣ may be the central mechanism by which latent TGF-␤ prevents renal inflammation.

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Section: Discussionmentioning

confidence: 99%

Signaling Mechanism of TGF-β1 in Prevention of Renal Inflammation

Wang¹,

Huang²,

Li³

et al. 2005

Journal of the American Society of Nephrology

230

231

View full text Add to dashboard Cite

show abstract

“…TGF-b1 is a well-known anti-inflammatory cytokine (Ashcroft et al, 1999;Dunker and Krieglstein, 2000), whereas NF-kB is a critical component of pro-inflammatory responses (Karin and Greten, 2005). In normal epithelial cells, TGF-b1 negatively regulates NF-kB transcriptional activity (Arsura et al, 1997;Azuma et al, 1999), while pro-inflammatory cytokines repress Smad-dependent transcription (Nagarajan et al, 2000;Verrecchia et al, 2003). The anti-inflammatory effect of TGF-b1 is likely mediated by Smads, as targeted disruption of Smad3 alleviates inflammation (Ashcroft et al, 1999) and Smad3/Smad4 mediates suppression of NF-kB signaling in renal inflammation (Bitzer et al, 2000;Wang et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

TAK1 is required for TGF-β1-mediated regulation of matrix metalloproteinase-9 and metastasis

Safina

et al. 2007

Oncogene

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Transforming growth factor-b 1 (TGF-b1) signaling in tumor cells has been implicated in tumor angiogenesis and metastasis by regulating matrix proteolysis. Although MMP-9/gelatinase-B is an important component of these TGF-b1 responses, the mechanism of its regulation is not well understood. Here, we present evidence that TGF-bactivated protein kinase 1 (TAK1) is critical for TGF-b regulation of MMP-9 and the metastatic potential of breast cancer cell line MDA-MB-231. We found that suppression of TAK1 signaling by dominant-negative (dn) TAK1 or RNA interference (siRNA) reduces expression of MMP-9 and tumor cell invasion, without growth inhibition in cell culture. The orthotopic xenograft studies in SCID mice showed that suppression of TAK1 signaling by dn-TAK1 reduces tumor growth and formation of lung metastases. QJ;Dn-TAK1 reduced the proliferation Ki-67 index and neovasculature of orthotopic xenografts. TAK1-mediated regulation of MMP-9 involves NF-jB signaling. Dn-TAK1 reduces NF-jB transcriptional response and inhibition of NF-jB reduces expression of MMP-9 and activity of the MMP-9 promoter reporter. Together, these findings suggest that TAK1 contributes to TGF-b1-mediated tumor angiogenesis and metastasis via a mechanism involving the TAK1-NF-jB-MMP-9 pathway.

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“…For instance, the Col1a1, Col3a1 and Serpinh1 promoters share four transcription factor binding sites, one of which is associated with NF-κB (see Table 1). In fact, NF-κB signaling has been found to influence collagen expression and accumulation (Novitskiy et al, 2004;Tang et al, 2004;Theiss et al, 2005;Nieto, 2007), and cross-talk between the NF-κB and TGF-β signaling pathways has been identified (Azuma et al, 1999;Hong et al, 2007). Describing how these factors influence collagen gene expression under CR will be an important task, since both TGF-β and NF-κB have a role in tumor development (de Caestecker et al, 2000;Sarkar and Li, 2008), and downregulation of Col1a1, Col3a1 and Serpinh1 by CR may contribute to increased lifespan by combating fibrosis in a variety of tissues (Wynn, 2008).…”

Section: Discussionmentioning

confidence: 99%

Genes regulated by caloric restriction have unique roles within transcriptional networks

Swindell

2008

Mechanisms of Ageing and Development

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Caloric restriction (CR) has received much interest as an intervention that delays age-related disease and increases lifespan. Whole-genome microarrays have been used to identify specific genes underlying these effects, and in mice, this has led to the identification of genes with expression responses to CR that are shared across multiple tissue types. Such CR-regulated genes represent strong candidates for future investigation, but have been understood only as a list, without regard to their broader role within transcriptional networks. In this study, co-expression and network properties of CR-regulated genes were investigated using data generated by more than 600 Affymetrix microarrays. This analysis identified groups of co-expressed genes and regulatory factors associated with the mammalian CR response, and uncovered surprising network properties of CR-regulated genes. Genes downregulated by CR were highly connected and located in dense network regions. In contrast, CR-upregulated genes were weakly connected and positioned in sparse network regions. Some network properties were mirrored by CR-regulated genes from invertebrate models, suggesting an evolutionary basis for the observed patterns. These findings contribute to a systems-level picture of how CR influences transcription within mammalian cells, and point towards a comprehensive understanding of CR in terms of its influence on biological networks.

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TGF-β1 Inhibits NF-κB Activity through Induction of IκB-α Expression in Human Salivary Gland Cells: A Possible Mechanism of Growth Suppression by TGF-β1

Cited by 58 publications

References 51 publications

Signaling Mechanism of TGF-β1 in Prevention of Renal Inflammation

Signaling Mechanism of TGF-β1 in Prevention of Renal Inflammation

TAK1 is required for TGF-β1-mediated regulation of matrix metalloproteinase-9 and metastasis

Genes regulated by caloric restriction have unique roles within transcriptional networks

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