Loss of receptors for transforming growth factor beta in human T-cell malignancies.

Kadin, Marshall E.; Cavaillé-Coll, M; Gertz, Robert E.; Massagué, Joan; Cheifetz, Sela; George, Diane

doi:10.1073/pnas.91.13.6002

Cited by 197 publications

(119 citation statements)

References 37 publications

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“…Several studies have shown that inactivation of TGF␤ receptors induces TGF␤ resistance and contributes to disease pathogenesis (21,22). In OA, dysfunction of TGF␤1 signaling may contribute to an insensitivity to TGF␤1 and lead to the degradation of articular cartilage.…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐1β impairment of transforming growth factor β1 signaling by DOWN‐REGULATION of transforming growth factor β receptor type II and up‐regulation of Smad7 in human articular chondrocytes

Baugé

Legendre

Leclercq

et al. 2007

Arthritis & Rheumatism

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Objective. Extracellular matrix deposition is tightly controlled by a network of regulatory cytokines. Among them, interleukin-1␤ (IL-1␤) and transforming growth factor ␤1 (TGF␤1) have been shown to play antagonistic roles in tissue homeostasis. The purpose of this study was to determine the influence of IL-1␤ on TGF␤ receptor type II (TGF␤RII) regulation and TGF␤1 responsiveness in human articular chondrocytes.Methods. TGF␤1-induced gene expression was analyzed through plasminogen activator inhibitor 1 and p3TP-Lux induction. Receptor-activated Smad (RSmad) phosphorylation, TGF␤ receptors, and Smad expression were determined by Western blotting and real-time reverse transcription-polymerase chain reaction techniques. Signaling pathways were investigated using specific inhibitors, messenger RNA (mRNA) silencing, and expression vectors.Results. IL-1␤ down-regulated TGF␤RII expression at both the protein and mRNA levels and led to inhibition of the TGF␤1-induced gene expression and Smad2/3 phosphorylation. Moreover, IL-1␤ strongly stimulated the expression of inhibitory Smad7.TGF␤RII overexpression abolished the loss of TGF␤1 responsiveness induced by IL-1␤. The decrease in TGF␤RII required de novo protein synthesis and involved both the NF-B and JNK pathways.Conclusion. We demonstrate that IL-1␤ impairs TGF␤1 signaling through down-regulation of TGF␤RII, which is mediated by the p65/NF-B and activator protein 1/JNK pathways, and secondarily through the up-regulation of Smad7. These findings show that there is cross-talk in the signaling of 2 regulatory cytokines involved in inflammation.

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Section: Discussionmentioning

confidence: 99%

Interleukin‐1β impairment of transforming growth factor β1 signaling by DOWN‐REGULATION of transforming growth factor β receptor type II and up‐regulation of Smad7 in human articular chondrocytes

Baugé

Legendre

Leclercq

et al. 2007

Arthritis & Rheumatism

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“…Second, decreased expression of either TbRI or TbRII has been implicated as a mechanism for TGF-b resistance in human tumors. TbRI underexpression occurs in prostate, colon, and pancreatic cancer cell lines, and in chronic lymphocytic leukemia cells (Baldwin et al, 1996;DeCoteau et al, 1997;Kim et al, 1996;Wang et al, 1996), whereas TbRII levels are low in gastric cancer cells and in TGF-bresistant T-cell lymphoma cells (Kadin et al, 1994;Park et al, 1994). Third, inactivating mutations in components of the TGF-b signaling pathway, such as Smad2 or Smad4 lead to a TGF-b-resistant state Eppert et al, 1996;Riggins et al, 1996;.…”

Section: Discussionmentioning

confidence: 99%

The TGF-β signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer

et al. 1999

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Transforming growth factor-beta (TGF-b) signaling is dependent on the heterodimerization of the type II TGFb receptor (TbRII) with the type I TGF-b receptor (TbRI). Activated TbRI then mediates TGF-b signals by inducing the phosphorylation of Smad2 and/or Smad3, which separately hetetorodimerize with Smad4 and translocate to the nucleus. Phosphorylation of Smad2/ Smad3 by activated TbRI is inhibited by two newly discovered members of the Smad family, Smad6 and Smad7. We now report that Smad7 mRNA levels are increased in human pancreatic cancer by comparison with the normal pancreas, and that by in situ hybridization, Smad7 is over-expressed in the cancer cells within the tumor mass. Stable transfection of COLO-357 human pancreatic cancer cells with a fulllength Smad7 construct leads to complete loss of the growth inhibitory response to TGF-b1, without altering TGF-b1-mediated induction of PAI-I. Furthermore, Smad7 transfected COLO-357 cells display enhanced anchorage-independent growth and accelerated growth in nude mice. These ®ndings point to a previously unrecognized mechanism for selective suppression of TGF-b-mediated growth inhibition in cancer cells that allows for continued activation of the PAI-I promoter by TGF-b1, which may act to enhance the tumorigenicity of certain cancer cells.

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“…However, a strong correlation between TGF-b RII mutation and microsatellite instability has been demonstrated, only for colon and gastric cancers (Eshleman and Markowitz, 1995;Kolodner, 1996;Markowitz et al, 1995;Modrich and Lahue, 1996;Myero et al, 1995;Parsons et al, 1995). Since then, defective expression of TGF-b RII has been demonstrated in gastric, colon, small-cell lung, breast, endometrial, hepatocellular, bladder, and squamous cell cancers as well as retinoblastoma, pheochromocytoma, osteosarcoma, and lymphomas (Chang et al, 1997;Garrigue-Antar et al, 1995;Inagaki et al, 1993;Kadin et al, 1994;Kim and Kim, 1996;Kimchi et al, 1988;Park et al, 1994;Markowitz et al, 1995;Markowitz and Roberts, 1996;Sun et al, 1994;Wang et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional repression of the transforming growth factor-β type I receptor gene by DNA methylation results in the development of TGF-β resistance in human gastric cancer

et al. 1999

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The transforming growth factor-b (TGF-b) signaling pathway subserves an essential tumor suppressor function in various cell types. A heteromeric complex composed of TGF-b type I (RI) and type II (RII) receptors is required for TGF-b signaling. We have identi®ed a subset of human gastric cancer cell lines which are insensitive to TGF-b and which express a low level of TGF-b type I receptor mRNA relative to a gastric cancer cell line which is highly responsive to TGF-b. Using these cells, we show that hypermethylation of a CpG island in the 5' region of the TGF-b RI gene provides another potentially important mechanism of escape from negative growth control by TGF-b. This hypermethylation was found in four of ®ve human gastric cancer cell lines and ®ve out of 40 (12.5%) primary tumors examined. In human gastric cancer cell lines, treatment with the demethylating agent, 5-aza-2'-deoxycytidine, resulted in increased expression of the TGF-b RI gene, but not the RII gene. Transient transfection of an RI expression vector into the TGF-b resistant SNU-601 cell line restores TGF-b responsiveness. These ®ndings suggest that one of the mechanisms of escape from autocrine or paracrine growth control by TGF-b during carcinogenesis could involve aberrant methylation of CpG islands in the 5' region of the TGF-b RI gene.

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Loss of receptors for transforming growth factor beta in human T-cell malignancies.

Abstract: Ki-1 (CD30)+ cute T-cell

Cited by 197 publications

References 37 publications

Interleukin‐1β impairment of transforming growth factor β1 signaling by DOWN‐REGULATION of transforming growth factor β receptor type II and up‐regulation of Smad7 in human articular chondrocytes

Interleukin‐1β impairment of transforming growth factor β1 signaling by DOWN‐REGULATION of transforming growth factor β receptor type II and up‐regulation of Smad7 in human articular chondrocytes

The TGF-β signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer

Transcriptional repression of the transforming growth factor-β type I receptor gene by DNA methylation results in the development of TGF-β resistance in human gastric cancer

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