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The role of Smad7 and TRAF6 in Prostate Cancer Cell Invasion, Migration and Survival
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research. (Apoptotic signaling group)
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 [en]
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: urn:nbn:se:uu:diva-159150ISBN: 978-91-554-8164-3 (print)OAI: oai:DiVA.org:uu-159150DiVA: diva2:442858
Public defence
2011-11-04, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-10-13 Created: 2011-09-22 Last updated: 2018-01-12Bibliographically approved
List of papers
1. TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer
Open this publication in new window or tab >>TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer
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2011 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 2, no 330Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor β (TGFβ) is a pluripotent cytokine promoting epithelial cell plasticity during morphogenesis and tumour progression. TGFβ binding to type II and type I serine/threonine kinase receptors (TβRII and TβRI) causes activation of different intracellular signaling pathways. TβRI is associated with the ubiquitin ligase tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). Here we show that TGFβ, via TRAF6, causes Lys63-linked polyubiquitination of TβRI, promoting cleavage of TβRI by TNF-alpha converting enzyme (TACE), in a PKCζ-dependent manner. The liberated intracellular domain (ICD) of TβRI associates with the transcriptional regulator p300 to activate genes involved in tumour cell invasiveness, such as Snail and MMP2. Moreover, TGFβ-induced invasion of cancer cells is TACE- and PKCζ- dependent and the TβRI ICD is localized in the nuclei of different kinds of tumour cells in tissue sections. Thus, our data reveal a specific role for TβRI in TGFβ mediated tumour invasion.

Place, publisher, year, edition, pages
Macmillan Publishers Limited, 2011
Keyword
TRAF6, TGF-beta, TGF-beta receptor I, cleavage, TACE, atypical PKC
National Category
Medical and Health Sciences
Research subject
Cell Research
Identifiers
urn:nbn:se:uu:diva-159148 (URN)10.1038/ncomms1332 (DOI)000294802600035 ()
Available from: 2011-09-22 Created: 2011-09-22 Last updated: 2017-12-08Bibliographically approved
2. APC and Smad7 link the TGFβ type I receptors to the microtubule system to promote cell migration
Open this publication in new window or tab >>APC and Smad7 link the TGFβ type I receptors to the microtubule system to promote cell migration
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2012 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 23, no 11, 2109-2121 p.Article in journal (Refereed) Published
Abstract [en]

Cell migration occurs by activation of complex regulatory pathways that are spatially and temporally integrated in response to extracellular cues. Binding of adenomatous polyposis coli (APC) to the microtubule plus ends in polarized cells is regulated by glycogen synthase kinase 3 beta (GSK-3 beta). This event is crucial for establishment of cell polarity during directional migration. However, the role of APC for cellular extension in response to extracellular signals is less clear. Smad7 is a direct target gene for transforming growth factor-beta (TGF beta) and is known to inhibit various TGF beta-induced responses. Here we report a new function for Smad7. We show that Smad7 and p38 mitogen-activated protein kinase together regulate the expression of APC and cell migration in prostate cancer cells in response to TGF beta stimulation. In addition, Smad7 forms a complex with APC and acts as an adaptor protein for p38 and GSK-3 beta kinases to facilitate local TGF beta/p38-dependent inactivation of GSK-3 beta, accumulation of beta-catenin, and recruitment of APC to the microtubule plus end in the leading edge of migrating prostate cancer cells. Moreover, the Smad7-APC complex links the TGF beta type I receptor to the microtubule system to regulate directed cellular extension and migratory responses evoked by TGF beta.

Keyword
APC, Smad7, GSK-3beta, p38, TGF-beta, cell migration
National Category
Medical and Health Sciences
Research subject
Cell Research
Identifiers
urn:nbn:se:uu:diva-159146 (URN)10.1091/mbc.E10-12-1000 (DOI)000306286400008 ()
Available from: 2011-09-22 Created: 2011-09-22 Last updated: 2017-12-08Bibliographically approved
3. Smad7 and APC are required for EGF-induced cell migration in human prostate epithelial cells
Open this publication in new window or tab >>Smad7 and APC are required for EGF-induced cell migration in human prostate epithelial cells
(English)Manuscript (preprint) (Other academic)
Keyword
EGF, EGFR, Smad7, APC, cell migration
National Category
Medical and Health Sciences
Research subject
Cell Research
Identifiers
urn:nbn:se:uu:diva-159149 (URN)
Available from: 2011-09-22 Created: 2011-09-22 Last updated: 2011-11-04
4. TGF beta 1-induced activation of ATM and p53 mediates apoptosis in a Smad7-dependent manner
Open this publication in new window or tab >>TGF beta 1-induced activation of ATM and p53 mediates apoptosis in a Smad7-dependent manner
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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.

Keyword
apoptosis, prostate cancer, p53, Smad, ATM
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-147029 (URN)000242897800016 ()17172861 (PubMedID)
Available from: 2011-02-23 Created: 2011-02-23 Last updated: 2017-12-11Bibliographically approved

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