Interaction and Functional Cooperation of PEBP2/CBF with Smads

Hanai, Jun; Chen, Lin Feng; Kanno, Takuji; Ohtani-Fujita, Naoko; Kim, Woo Young; Guo, Wei; Imamura, Takeshi; Ishidou, Yasuhiro; Fukuchi, Minoru; Shi, M.; Stavnezer, Janet; Kawabata, Masahiro; Miyazono, Kohei; Ito, Yoshiaki

doi:10.1074/jbc.274.44.31577

Cited by 415 publications

(127 citation statements)

References 45 publications

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“…However, the mechanisms that regulate the target genes remain to be resolved. Interestingly, RUNX2 interacts with AP-1 as well as Smads (Hanai et al, 1999;Hess et al, 2001). If RUNX3 also interacts with AP-1, it may be that some of the target genes of the TGF-b signaling pathway are cooperatively regulated by Smads, AP-1 and RUNX3.…”

Section: Mechanisms Underlying the Tumor Suppressor Activity Of Runx3mentioning

confidence: 99%

“…p300, which transmits TGF-b signaling synergistically with Smads, is also mutated in several cancers (Gayther et al, 2000). Notably, RUNX proteins physically interact with Smads and p300 and function synergistically (Kitabayashi et al, 1998;Hanai et al, 1999;Lee et al, 2000;Zhang et al, 2000). The fact that Smad2, Smad4, p300 and RUNX3 all function as tumor suppressors (Ito and Miyazono, 2003) suggests that all these components are required for the tumor suppressor activity of the TGF-b signaling pathway.…”

Section: Mechanisms Underlying the Tumor Suppressor Activity Of Runx3mentioning

confidence: 99%

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Tumor suppressor activity of RUNX3

2004

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Recent analyses have revealed that RUNX family members play important roles in both normal developmental processes and carcinogenesis. Of the three known RUNX family members, RUNX3 has been shown to be involved in neurogenesis of the dorsal root ganglia, T-cell differentiation and tumorigenesis of gastric epithelium. Deletion of the Runx3 locus in mice resulted in hyperplasia of the gastric epithelium due to the stimulation of proliferation and suppression of apoptosis that was accompanied by a reduced sensitivity to TGF-b1. In primary human gastric cancer specimens, RUNX3 is frequently inactivated by allele loss or gene silencing due to promoter hypermethylation. The tumorigenicity of human gastric cancer cell lines in nude mice decreased as the level of RUNX3 expression increased, which indicates that RUNX3 is a bona fide tumor suppressor of gastric cancers.

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Section: Mechanisms Underlying the Tumor Suppressor Activity Of Runx3mentioning

confidence: 99%

Section: Mechanisms Underlying the Tumor Suppressor Activity Of Runx3mentioning

confidence: 99%

Tumor suppressor activity of RUNX3

2004

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“…Smad2 is unable to bind directly to DNA because it contains an extra exon just N-terminal of the b-hairpin loop (Dennler et al, 1998;Yagi et al, 1999). SBE-like sequences have been identi®ed in the promoters of multiple TGF-b responsive genes, including plasminogen activator inhibitor-1 (PAI-1) (Dennler et al, 1998;Luo et al, 1999), junB (Jonk et al, 1998), type VII collagen (Vindevoghel et al, 1998) and the germline immunoglobulin Ia region (Hanai et al, 1999;Pardali et al, 2000a;Zhang and Derynck, 2000). Mutation of SBEs attenuate TGF-b inducibility.…”

Section: Introductionmentioning

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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“…However, when placed in the appropriate context, RUNX family members act as organizing factors at the promoters and enhancers of target genes where they associate with cofactors and other DNA-binding transcription factors that are required for gene regulation. These factors include C/EBPa (Zhang et al, 1996;Westendorf et al, 1998), ETS family members (Giese et al, 1995;Petrovick et al, 1998;Kim et al, 1999;Mao et al, 1999), SMADs (Hanai et al, 1999;Gu et al, 2000;Jakubowiak et al, 2000;Pardali et al, 2000;Zhang and Derynck, 2000) and histone acetyltransferases including p300/CBP (Kitabayashi et al, 1998;Pelletier et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Role of RUNX family members in transcriptional repression and gene silencing

2004

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RUNX family members are DNA-binding transcription factors that regulate the expression of genes involved in cellular differentiation and cell cycle progression. The RUNX family includes three mammalian RUNX proteins (RUNX1, -2, -3) and two homologues in Drosophila. Experiments in Drosophila and mouse indicate that the RUNX proteins are required for gene silencing of engrailed and CD4, respectively. RUNX-mediated repression involves recruitment of corepressors such as mSin3A and Groucho as well as histone deacetylases. Furthermore, RUNX1 and RUNX3 associate with SUV39H1, a histone methyltransferase involved in gene silencing. RUNX1 is frequently targeted in human leukemia by chromosomal translocations that fuse the DNA-binding domain of RUNX1 to other transcription factors and corepressor molecules. The resulting leukemogenic fusion proteins are transcriptional repressors that form stable complexes with corepressors, histone deacetylases and histone methyltransferases. Thus, transcriptional repression and gene silencing through RUNX1 contribute to the mechanisms of leukemogenesis of the fusion proteins. Therapies directed at the associated cofactors may be beneficial for treatment of these leukemias.

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Interaction and Functional Cooperation of PEBP2/CBF with Smads

Cited by 415 publications

References 45 publications

Tumor suppressor activity of RUNX3

Tumor suppressor activity of RUNX3

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

Role of RUNX family members in transcriptional repression and gene silencing

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