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PARP-1 attenuates Smad-mediated transcription
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.
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2010 (English)In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 40, no 4, 521-532 p.Article in journal (Refereed) Published
Abstract [en]

The versatile cytokine transforming growth factor β (TGF-β) regulates cellular growth, differentiation, and migration during embryonic development and adult tissue homeostasis. Activation of TGF-β receptors leads to phosphorylation of Smad2 and Smad3, which oligomerize with Smad4 and accumulate in the nucleus where they recognize gene regulatory regions and orchestrate transcription. Termination of Smad-activated transcription involves Smad dephosphorylation, nuclear export, or ubiquitin-mediated degradation. In an unbiased proteomic screen, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a Smad-interacting partner. PARP-1 dissociates Smad complexes from DNA by ADP-ribosylating Smad3 and Smad4, which attenuates Smad-specific gene responses and TGF-β-induced epithelial-mesenchymal transition. Thus, our results identify ADP-ribosylation of Smad proteins by PARP-1 as a key step in controlling the strength and duration of Smad-mediated transcription.

Place, publisher, year, edition, pages
2010. Vol. 40, no 4, 521-532 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-128847DOI: 10.1016/j.molcel.2010.10.029ISI: 000284988400006PubMedID: 21095583OAI: oai:DiVA.org:uu-128847DiVA: diva2:331941
Available from: 2010-07-28 Created: 2010-07-27 Last updated: 2012-08-01Bibliographically approved
In thesis
1. Regulation of TGF-β Signaling by Post-Translational Modifications
Open this publication in new window or tab >>Regulation of TGF-β Signaling by Post-Translational Modifications
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transforming growth factor-β (TGF-β) signaling is initiated when the ligand binds to type II and type I serine/threonine kinase receptors at the cell surface. Activated TGF-β type I receptors phosphorylate R-Smads which relocate, together with co-Smads, to the cell nucleus and regulate transcription. Enhancement or repression of Smad-specific gene targets leads to intracellular protein compositions which organize functional complexes and thus govern cellular processes such as proliferation, migration and differentiation.

TGF-β/Smad signaling relays are regulated by various post-translational modifications. From receptors to gene promoters, intricate interplays between phosphorylation, acetylation, ubiquitination and numerous other modifications, control Smad signaling initiation and duration. However, many steps in the cascade, including receptor internalization, Smad nuclear shuttling and transcriptional termination, still remain elusive. The open gaps in our understanding of these mechanisms most likely involve additional post-translational regulations. Thus, the aim of the present investigation was to identify novel modulators of TGF-β/Smad signaling.

In the first part of this thesis, we show the importance of ADP-ribosylation in Smad-mediated transcription. We identified poly(ADP-ribose) polymerase 1 (PARP-1) as a Smad interacting protein. Our work revealed that PARP-1 forms direct interactions with Smad3/4, and PARylates residues in their MH1 domains. This modification restricts Smads from binding to DNA and attenuates Smad-activated transcription. PARylation is reversed by the glycohydrolase PARG. We provide evidence that PARG can de-ADP-ribosylate Smads, which enhances Smad-promoted gene regulation.

In the second part, we examine a Smad-dependent gene target of TGF-β signaling, salt inducible kinase 1 (SIK). After induction, SIK cooperates with Smad7 and Smurf2 to downregulate the TGF-β type I receptor. The mechanism relies on both the kinase and UBA domain of SIK as well as the E3-ligase activity of Smurf2.

In summary, we have unveiled two enzyme-dependent TGF-β/Smad modulatory mechanisms; SIK promoted receptor turnover and PARP-1/PARG-regulated Smad signaling.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 577
Keyword
TGF-β, Smad, PARP-1, PARG, ALK5, SIK, signal transduction, transcription, post-translational modification, phosphorylation, ubiquitin, ADP-ribosylation, DNA-binding, receptor degradation
National Category
Biochemistry and Molecular Biology
Research subject
Biology with specialization in Molecular Cell Biology
Identifiers
urn:nbn:se:uu:diva-128855 (URN)978-91-554-7844-5 (ISBN)
Public defence
2010-09-10, Room B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2010-08-20 Created: 2010-07-27 Last updated: 2010-08-30Bibliographically approved
2. Mechanisms for Quantitative Regulation of TGF-ß Signaling
Open this publication in new window or tab >>Mechanisms for Quantitative Regulation of TGF-ß Signaling
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer is a widely spread disease, and many cancer variants are today still difficult to treat. Efforts are being made to understand the complexity of cancer, both at a clinical level but also at a pre-clinical level. The aim is of course to merge the research from both disciplines, as an example, find out how to treat a tumour in a patient and what molecular mechanisms are behind the origin of the tumour. Basic research provides a platform that in the long run will help to create treatments for many cancer variants that exist today. Transforming Growth Factor Beta (TGF-ß) is a cytokine that regulates many cellular events such as cell differentiation, cell proliferation and migration. TGF-ß signaling is important to study since many studies show that patients with cancer actually have accumulated mutations in proteins connected to the pathway. In this thesis I try to enhance the knowledge of the TGF-ß signaling pathway, looking in more detail how the signaling output is regulated by the response to the ligand, explained in paper four. Furthermore I try to reveal the protein network that control transmission of the signal from the cell surface to the nucleus. We found that PARP-1 (paper one and two) and PARP-2 (paper three) associates with the signaling pathway to regulate the Smad proteins and to negatively regulate the transcription of Smad target genes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 41 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 767
National Category
Natural Sciences Cell Biology
Research subject
Biology with specialization in Molecular Cell Biology
Identifiers
urn:nbn:se:uu:diva-172855 (URN)978-91-554-8351-7 (ISBN)
Public defence
2012-06-07, B42, Biomedical Center (BMC), Husargatan 3, C11, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2012-05-14 Created: 2012-04-16 Last updated: 2012-08-01Bibliographically approved

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