uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
The DNA Binding Activities of Smad2 and Smad3 Are Regulated by Coactivator-mediated Acetylation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Show others and affiliations
2006 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, no 52, 39870-39880 p.Article in journal (Refereed) Published
Abstract [en]

Phosphorylation-dependent activation of the transcription factors Smad2 and Smad3 plays an important role in TGFbeta-dependent signal transduction. Following phosphorylation of Smad2 and Smad3, these molecules are translocated to the nucleus where they interact with coactivators and/or corepressors, including p300, CBP, and P/CAF, and regulate the expression of TGFbeta target genes. In the current study, we demonstrate that both Smad2 and Smad3 are acetylated by the coactivators p300 and CBP in a TGFbeta-dependent manner. Smad2 is also acetylated by P/CAF. The acetylation of Smad2 was significantly higher than that of Smad3. Lys(19) in the MH1 domain was identified as the major acetylated residue in both the long and short isoform of Smad2. Mutation of Lys(19) also reduced the p300-mediated acetylation of Smad3. By generating acetyl-Lys(19)-specific antibodies, we demonstrate that endogenous Smad2 is acetylated on this residue in response to TGFbeta signaling. Acetylation of the short isoform of Smad2 improves its DNA binding activity in vitro and enhances its association with target promoters in vivo, thereby augmenting its transcriptional activity. Acetylation of Lys(19) also enhanced the DNA binding activity of Smad3. Our data indicate that acetylation of Lys(19) induces a conformational change in the MH1 domain of the short isoform of Smad2, thereby making its DNA binding domain accessible for interactions with DNA. Thus, coactivator-mediated acetylation of receptor-activated Smad molecules could represent a novel way to regulate TGFbeta signaling.

Place, publisher, year, edition, pages
2006. Vol. 281, no 52, 39870-39880 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95510DOI: 10.1074/jbc.M607868200ISI: 000243033900014PubMedID: 17074756OAI: oai:DiVA.org:uu-95510DiVA: diva2:169753
Available from: 2007-10-10 Created: 2007-10-10 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Protein Acetylation – A Multifunctional Regulator of TGF-β Signaling
Open this publication in new window or tab >>Protein Acetylation – A Multifunctional Regulator of TGF-β Signaling
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transforming growth factor β (TGF-β) is a member of a large family of cytokines that regulate many crucial events in cells, including proliferation, differentiation, migration and apoptosis. Deregulated TGF-β signaling is associated with various forms of cancers and developmental disorders. TGF-β binds to a receptor complex at the surface of cells and activates a signaling cascade involving specific intracellular signaling proteins, known as Smads. Following receptor activation, the Smads are activated by phosphorylation and translocate to the nucleus, where they activate or repress the expression of specific genes.

Posttranslational modifications regulate the function of proteins in a number of ways, including their activity, stability, localization, and/or interactions with other proteins. These modifications are important to modulate the strength and specificity of cellular signal transduction. Smad7, an important negative modulator of TGF-β signaling, has been shown to be acetylated by the acetyltransferase p300. My aim was to further explore the involvement of protein acetylation in TGF-β-dependent signaling.

We could show that the acetylation of Smad7 is a reversible process. Interestingly, earlier work had shown that the acetylation of Smad7 prevented its degradation. In agreement with this observation, we found that the ubiquitylation and degradation of Smad7 was increased following cotransfection with HDAC1, a protein deacetylase. Based on our observations, we propose a model in which the stability of Smad7 is controlled by the balance between its acetylation, deacetylation and ubiquitylation. In a separate study, we found that also Smad2 and Smad3 are acetylated by p300/CBP and P/CAF upon TGF-β stimulation. Moreover, we found that the acetylation of the short isoform of Smad2 promoted its DNA binding activity, resulting in an increased transcriptional activity. Our results suggest that the increased DNA binding in response to acetylation is due to a conformational change in Smad2.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 232
Keyword
Cell biology, TGF-β, Acetylation, Deacetylation, Acetyltransferase, HDAC, Smad, Transcription, Cellbiologi
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-7596 (URN)978-91-554-6811-8 (ISBN)
Public defence
2007-03-30, B22, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-04-21 Created: 2007-10-10 Last updated: 2009-04-21Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed
By organisation
Ludwig Institute for Cancer Research
In the same journal
Journal of Biological Chemistry
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 500 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf