Comparative mutational analysis of DPC4 (Smad4) in prostatic and colorectal carcinomas

MacGrogan, Donal; Pegram, Mark D.; Slamon, Dennis J.; Bookstein, Robert

doi:10.1038/sj.onc.1201232

Cited by 114 publications

(80 citation statements)

References 19 publications

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“…In addition, attenuation of the TGF␤1 response may also be due to a diminished level of intracellular TGF␤1 signaling molecules (R-Smad and/or Co-Smad) or an up-regulation of intracellular inhibitors (I-Smad) (26,27). While the levels of mRNA for Smads 2, 3, and 4 were not affected by IL-1␤, the levels of Smad7 mRNA and protein were increased.…”

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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“…This insensitivity to the negative growth control by TGF-b1 may be due to mutations in its receptors or its signaling proteins (i.e. the MAD and MAD-related proteins), which have been identi®ed in approximately 15% of colorectal cancers Eppert et al, 1996;MacGrogan et al, 1997). TGF-b type II receptor expression is decreased in intestinal adenomas of mouse with germline mutation in the APC gene and is associated with increased expression of cyclin D1 and Cdk4 (Zhang et al, 1997a, b).…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

Sakai

et al. 1998

Oncogene

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Transforming growth factor-beta 1 (TGF-b1) arrests intestinal epithelial cells (RIE-1 and IEC-6) in the G1 phase of the cell cycle and inhibits cyclin D1 expression. This report describes experiments designed to elucidate the mechanism of cyclin D1 inhibition and to determine whether inhibition of cyclin D1 expression is the cause, rather than the result, of TGF-b1-mediated cell cycle arrest. TGF-b1 inhibition of IEC-6 cell proliferation was associated with a decrease in the abundance of cyclin D1/Cdk4 complexes and a corresponding decrease in Cdk4-dependent phosphorylation of the retinoblastoma protein. Metabolic labeling studies indicated that TGFb1 inhibited cyclin D1 synthesis without altering the rate of cyclin D1 protein degradation. Cyclin D1 antisense oligonucleotides blocked serum-stimulated induction of cyclin D1 and DNA synthesis, whereas cyclin D1 sense oligonucleotides had no e ect. RIE-1 cells were engineered to overexpress human cyclin D1 under the control of a tetracycline-repressible promoter. These cells entered S phase in the presence of TGF-b1 only when human cyclin D1 was derepressed by the withdrawal of tetracycline. These data indicate that TGF-b1 inhibits the synthesis of cyclin D1 in gut epithelial cells and that this inhibition is the cause, rather than the result, of TGF-b1-mediated arrest of intestinal epithelial cell proliferation.

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“…The two residues of the b-hairpin loop that were mutated to abolish DNA binding, and the missense mutations in Smad4 analysed in the present study, are indicated. Numbers indicate amino acid sequence relative to the initiation codon identi®ed in colorectal cancer (MacGrogan et al, 1997). Since this residue is completely solvent-exposed and located in a loop region, it may possibly be involved in interactions with other proteins .…”

Section: Missense Mutations In the Smad4 Amino-terminal Domainmentioning

confidence: 99%

Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4

et al. 2000

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Smads, the intracellular e ectors of transforming growth factor-b (TGF-b) family members, are somatically mutated at high frequency in particular types of human cancers. Certain of these mutations a ect the Smad amino-terminal domain, which, in the case of Smad3 and Smad4, binds DNA. We investigated the functional consequences of four missense mutations in the Smad4 amino-terminal domain found in human tumors. The mutant proteins were found to have impaired abilities to bind DNA although they were fully capable of forming complexes with Smad3. All four Smad4 mutants showed decreased protein stability compared to wild-type Smad4. Two of the Smad4 mutants (G65V and P130S) were translocated to the nucleus and were capable of transactivating a Smad-dependent promoter in a liganddependent manner. In contrast, the L43S and R100T mutants were not translocated e ciently to the nucleus and consequently resulted in severely defective transcriptional responses to TGF-b. Moreover, we demonstrate here the critical importance of two basic residues in the b-hairpin loop of Smad3 or Smad4 for DNA binding, consistent with predictions from the Smad3 crystal structure. In addition, our results reveal that in the TGF-b-induced heteromeric signaling complex, loss of DNA binding of Smad4 can be compensated by Smad3, however, both Smad3 and Smad4 are needed for e cient DNA binding and signaling. In conclusion, mutations in the amino-terminal domain of Smad4, that are found in cancer, show loss of multiple functional properties which may contribute to tumorigenesis. Oncogene (2000) 19, 4396 ± 4404.

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Comparative mutational analysis of DPC4 (Smad4) in prostatic and colorectal carcinomas

Cited by 114 publications

References 19 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

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4

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