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The balance between acetylation and deacetylation controls Smad7 stability
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.
2005 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 280, no 23, 21797-21803 p.Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor beta (TGFbeta) regulates multiple cellular processes via activation of Smad signaling pathways. We have recently demonstrated that the inhibitory Smad7 interacts with the acetyl transferase p300 and that p300 acetylates Smad7 on two lysine residues. These lysine residues are critical for Smurf-mediated ubiquitination of Smad7, and acetylation protects Smad7 from TGFbeta-induced degradation. In this study we demonstrate that Smad7 interacts with specific histone deacetylases (HDACs) and that the same HDACs are able to deacetylate Smad7. The interaction with HDACs is dependent on the C-terminal MH2 domain of Smad7. In addition, HDAC1-mediated deacetylation of Smad7 decreases the stability of Smad7 by enhancing its ubiquitination. Thus, our results demonstrate that the degradation of Smad7 is regulated by the balance between acetylation, deacetylation and ubiquitination, indicating that this could be a general mechanism to regulate the stability of cellular proteins.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology , 2005. Vol. 280, no 23, 21797-21803 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95509DOI: 10.1074/jbc.M503134200PubMedID: 15831498OAI: oai:DiVA.org:uu-95509DiVA: diva2:169752
Available from: 2007-10-10 Created: 2007-10-10 Last updated: 2010-08-13Bibliographically 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

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Heldin, Carl-Henrik

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