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TGF beta 1-induced activation of ATM and p53 mediates apoptosis in a Smad7-dependent manner
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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2006 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 5, no 23, 2787-2795 p.Article in journal (Refereed) Published
Abstract [en]

ATM, a DNA-damage sensitive kinase and p53, are frequently inactivated in a variety of cancers as they together with gamma H2AX are critical guardians against DNA damage. Here, we report of a functional cross-talk between the cytokine TGF beta and p53, leading to apoptosis of epithelial cells, involving Smad7, a TGF beta target gene, p38 MAP kinase, and ATM. Using ectopic expression of p53, siRNA for Smad7, p38a(-/-) deficient cells and specific inhibitors, we show that TGF-beta induces apoptosis via ATM and p53 in epithelial cells. Intriguingly, Smad7 act as a scaffold protein to promote functional interactions between p38, ATM and p53 upon TGF beta treatment, facilitating their activation. Smad7. colocalizes with gamma H2AX in DNA damage foci and was required for proper cell cycle checkpoints to prevent genetic instability. Our data imply that Smad7 plays a crucial role upstream of ATM and p53 to protect the genome from insults evoked by extracellular stress.

Place, publisher, year, edition, pages
2006. Vol. 5, no 23, 2787-2795 p.
Keyword [en]
apoptosis, prostate cancer, p53, Smad, ATM
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-147029ISI: 000242897800016PubMedID: 17172861OAI: oai:DiVA.org:uu-147029DiVA: diva2:399788
Available from: 2011-02-23 Created: 2011-02-23 Last updated: 2017-12-11Bibliographically approved
In thesis
1. The role of Smad7 and TRAF6 in Prostate Cancer Cell Invasion, Migration and Survival
Open this publication in new window or tab >>The role of Smad7 and TRAF6 in Prostate Cancer Cell Invasion, Migration and Survival
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transforming growth factor (TGF) β is a tumor suppressor during early tumor development, by inhibiting proliferation and inducing apoptosis. At later stages of cancer, it becomes a tumor promoter, and promotes tumor cell migration and invasion. TGFβ signals via its type II and type I receptors to several downstream signaling pathways. In the present work we have focused on the TRAF6 (tumor necrosis factor receptor-associated factor 6)/ TAK1 (TGFβ activated kinase 1) signaling pathway and the Smad7-dependent activation of p38 in prostate carcinoma cells (PC3U). We found that TGFβ-induced activation of the ubiquitin ligase TRAF6 was needed for cell invasion, by a mechanism that involves activation of the metalloproteinase TNFα converting enzyme (TACE), via protein kinase Cζ (PKCζ). TACE cleaves the TβRI, whereafter the intracellular domain (ICD) translocates to the nucleus, where it binds to the transcriptional co-activator p300 and regulates gene expression, promoting invasion. Interestingly, the translocation of the TβRI ICD was observed in several cancer cell lines and in sections of primary tumors, but not in primary prostate epithelial cells. We also found that Smad7 and adenomatous polyposis coli (APC) are important for TGFβ- and epidermal growth factor (EGF)-induced cell migration in PC3U cells. TGFβ induces the formation of a complex consisting of Smad7, p38, glycogene synthase kinase 3β (GSK-3β), APC and β-catenin, which localizes to the membrane ruffles in the leading edge of migrating cells. The complex links the TβRI to the microtubule system and promotes membrane ruffling and microtubule polarization, which are known to be important for cell migration. In the EGF signaling pathway, Smad7 was found to be important for phosphorylation of the EGF receptor at Tyr1068, for the activation of p38 and JNK, and for induction of membrane ruffles. Smad7 is required for TGFβ-induced activation of p38 and apoptosis. We found that Smad7 forms a complex with p38 and ataxia telangiectasia mutated (ATM), which is important for activation of p53 mediated apoptosis. Many tumor cells including the PC3U cells lack a functional p53, which is one of the reasons to why cancer cells can avoid the tumor suppressor effects of TGFβ.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 705
Keyword
TGF-beta, cell migration, invasion, apoptosis, Smad7, APC, ATM, TRAF6, p53, PC3U
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-159150 (URN)978-91-554-8164-3 (ISBN)
Public defence
2011-11-04, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2011-10-13 Created: 2011-09-22 Last updated: 2012-05-01Bibliographically approved

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Heldin, Carl-Henrik

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