Drosophila Mad binds to DNA and directly mediates activation of vestigial by Decapentaplegic

Kim, Jaeseob; Johnson, Kirby D.; Chen, Hui Ju; Carroll, Sean B.; Laughon, Allen

doi:10.1038/40906

Cited by 493 publications

(413 citation statements)

References 7 publications

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“…EMSA with radiolabeled SBE probe showed that, in contrast to wild-type Smad4, all mutant proteins containing the complete coding region (data not shown) or lacking the carboxy-terminal domain (Figure 2), were unable to bind DNA. This ®nding is in agreement with Kim et al (1997), who showed that an equivalent mutation of R100T Smad4 in a carboxy-terminally truncated Drosophila Mad, resulted in a protein unable to bind to DNA. In addition, the lack of DNA binding of R100T Smad4 and P130S Smad4 mutants was recently shown by other research groups (Le Luo et al, 1999).…”

Section: Smad4 With Missense Mutations Have Reduced Ability To Bind Dnasupporting

confidence: 91%

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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Section: Smad4 With Missense Mutations Have Reduced Ability To Bind Dnasupporting

confidence: 91%

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

et al. 2000

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“…The MH1 domain of Drosophila Mad (Smad1/5/8) was found to bind DPP responsive regulatory regions in the vestigial, labial, and Ultrabithorax (Ubx) genes and interacts with the consensus sequence 5Ј-GCCGNCGC-3Ј (Kim et al, 1997). Vertebrate BMP R-Smads seem to have a similar GC-rich binding site preference Ishida et al, 2000) but many variations in sequence have since been reported.…”

Section: It's a Smad World: Dna Recognition By The Smadsmentioning

confidence: 99%

Finding partners: How BMPs select their targets

Blitz

Cho

2009

Developmental Dynamics

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The bone morphogenetic protein (BMP) signaling pathway is a conserved and evolutionarily ancient regulatory module affecting a large variety of cellular behaviors. The evolutionary flexibility in using BMP responses presumably arose by co-option of a canonical BMP signaling cascade to regulate the transcription of diverse batteries of target genes. This begs the question of how seemingly interchangeable BMP signaling components elicit widely different outputs in different cell types, an important issue in the context of understanding how BMP signaling integrates with gene regulatory networks to control development. Because a molecular understanding of how BMP signaling activates different batteries of target genes is an essential prerequisite to comprehending the roles of BMPs in regulating cellular responses, here we review the current knowledge of how BMP-regulated target genes are selected by the signal transduction machinery. We highlight recent studies suggesting the evolutionary conservation of BMP target gene regulation signaling by Schnurri family zinc finger proteins.

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“…Smads 1 and 5 directly binds to DNA; however, the affinity is relatively low and interaction with sequence-specific DNA binding proteins is critical for the formation of a stable DNA-binding complex (Derynck et al, 1998). The first demonstration that Smads can directly bind to DNA was reported in Drosophila (Kim et al, 1997). Vestigial, labial and ultrabithorax (Ubx) are decapentaplegic (dpp)-responsive genes.…”

Section: Bmp Signal Transductionmentioning

confidence: 99%

The BMP signaling and in vivo bone formation

Cao

Chen

2005

Gene

272

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Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor β(TGFβ) superfamily. The roles of BMPs in embryonic development and cellular functions in postnatal and adult animals have been extensively studied in recent years. Signal transduction studies have revealed that Smads 1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction. Studies from transgenic and knockout mice and from animals and humans with naturally occurring mutations in BMPs and their signaling molecules have shown that BMP signaling plays critical roles in bone and cartilage development and postnatal bone formation. BMP activities are regulated at different molecular levels. Tissue-specific knockout of a specific BMP ligand, a subtype of BMP receptors or a specific signaling molecule is required to further determine the specific role of a BMP ligand, receptor or signaling molecule in a particular tissue.

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Drosophila Mad binds to DNA and directly mediates activation of vestigial by Decapentaplegic

Cited by 493 publications

References 7 publications

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

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

Finding partners: How BMPs select their targets

The BMP signaling and in vivo bone formation

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