Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta

Yang, Xiao; Letterio, John J.; Lechleider, Robert J.; Chen, Lin; Hayman, Russ; Gu, Hua; Roberts, Anita B.; Deng, Chu‐Xia

doi:10.1093/emboj/18.5.1280

Cited by 819 publications

(825 citation statements)

References 59 publications

(75 reference statements)

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“…To determine if loss of Smad3 results in the loss of CEA expression in gastric mucosa, we examined CEA expression in the stomachs of Smad3 wild-type and Smad3 null mice. Expression of CEAs was also observed in the surface mucosal epithelium of the stomach of wild-type mice and correlated well with expression of Smad3 (Yang et al, 1999) (Figure 7). In contrast, expression of CEA was markedly decreased in the stomach of Smad3 null mice (Figure 7), suggesting that its expression is dependent, in part, on Smad3.…”

Section: Expression Of Wild-type Tbrii Restores Tgf-b Signaling and Isupporting

confidence: 57%

CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-β signaling

et al. 2007

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The carcinoembryonic antigen (CEAs) family consists of a large group of evolutionarily and structurally divergent glycoproteins. The transforming growth factor-b (TGF-b) signaling pathway has been implicated in the stimulation of CEA secretion in TGF-b-sensitive colon cells, thereby possibly modulating cell adhesion and differentiation. However, the specific CEAs targeted by TGF-b signaling or underlying mechanism of the expression of CEAs has not yet been clarified. In this study, we investigated the specific CEAs targeted by the TGF-b signaling pathway. In nine human gastric cancer cell lines examined, TGF-bresponsive cell lines showed positive expression of CEAs. Expression patterns of CEA proteins correlated well with the level of CEA (CEACAM5) and CEACAM6 transcripts in these cell lines, but CEACAM1 expression was not observed in all of these cells. To investigate the role of TGF-b signaling in CEA expression, we selected two TGFb unresponsive gastric cancer cell lines; SNU638 cells that contain a mutation in the TGF-b type II receptor and SNU484 cells that express low to undetectable level of the TGF-b pathway intermediate protein, Smad3. Restoration of TGF-b signaling in these cells induced expression of the CEAs and increased activity of both CEA (CEACAM5) and CEACAM6 promoters. CEA expression was observed in the epithelium of the stomach of wild-type mice, but was markedly decreased in Smad3 null mice. These findings suggest that CEA (CEACAM5) and CEACAM6 are major target genes for Smad3-mediated TGF-b signaling.

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Section: Expression Of Wild-type Tbrii Restores Tgf-b Signaling and Isupporting

confidence: 57%

CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-β signaling

et al. 2007

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“…However, this phenotype was not observed by others where the mice died between 1 and 8 months after birth due to chronic infections. Loss of Smad3 was found to result in an impaired mucosal immunity and the T-cell response to TGF-b was diminished Yang et al, 1999b). Furthermore, mice lacking Smad3 exhibit an accelerated wound healing due to an increased rate of re-epithelialization and reduced local in®ltration of monocytes (Ashcroft et al, 1999).…”

Section: Smad Knock-out Micementioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

398

278

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Transforming growth factor-b (TGF-b) family members which include TGF-bs, activins, and bone morphogenetic proteins (BMPs) regulate a broad spectrum of biological responses on a large variety of cell types. TGF-b family members initiate their cellular responses by binding to distinct receptors with intrinsic serine/ threonine kinase activity and activation of speci®c downstream intracellular effectors termed Smad proteins. Smads relay the signal from the cell membrane to the nucleus, where they affect the transcription of target genes. Smad activation, subcellular distribution, and stability have been found to be intricately regulated and a broad array of transcription factors have been identi®ed as Smad partners. Important activities of TGF-b are its potent anti-mitogenic and pro-apoptotic effects that, at least in part, are mediated via Smad proteins. Escape from TGF-b/ Smad-induced growth inhibition and apoptosis is frequently observed in tumors. Certain Smads have been found to be mutated in speci®c types of cancer and gene ablation of particular Smads in mice has revealed increased rate of tumorigenesis. In late stage tumors, TGF-b has been shown to function as a tumor promoter. TGFb can stimulate the de-differentiation of epithelial cells to malignant invasive and metastatic ®broblastic cells. Interestingly, TGF-b may mediate these effects directly on tumor cells via subverted Smad-dependent and/or Smad-independent pathways.

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“…To investigate the need for direct DNA binding of Smad3 and/or Smad4 in TGF-b-induced transcriptional responses that are mediated through SBEs in target promoters, we transfected the Smad3 or Smad4 b-hairpin mutants, alone or together with wild-type Smads, in Smad-de®cient cells and analysed for TGFb-induced SBE-reporter activity. Spontaneously immortalized mouse embryo ®broblasts (MEFs) lacking Smad3, derived from embryos with homozygous deletion of Smad3 (Yang et al, 1999), were used. The insensitivity to TGF-b-induced SBE-mediated transcriptional response of these cells could be rescued by cotransfection of wild-type Smad3; a substantial background was seen also in the absence of stimulation with TGF-b (Figure 6b) as noted before in Smad3 knock-out MEFs and other cell systems (Dennler et al, 1998;Yang et al, 1999;Zawel et al, 1998).…”

Section: Smad3 Can Complement Dna Binding Impaired Smad4 Mutantsmentioning

confidence: 99%

“…Spontaneously immortalized mouse embryo ®broblasts (MEFs) lacking Smad3, derived from embryos with homozygous deletion of Smad3 (Yang et al, 1999), were used. The insensitivity to TGF-b-induced SBE-mediated transcriptional response of these cells could be rescued by cotransfection of wild-type Smad3; a substantial background was seen also in the absence of stimulation with TGF-b (Figure 6b) as noted before in Smad3 knock-out MEFs and other cell systems (Dennler et al, 1998;Yang et al, 1999;Zawel et al, 1998). The R74K Smad3, K81R Smad3 and double R74K/K81R Smad3 (D3) b-hairpin mutants were unable to rescue the Smad3 de®ciency in these cells with respect to SBEreporter activity.…”

Section: Smad3 Can Complement Dna Binding Impaired Smad4 Mutantsmentioning

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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Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta

Cited by 819 publications

References 59 publications

CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-β signaling

CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-β signaling

Regulation of cell proliferation by Smad proteins

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

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