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Transforming growth factor-beta1-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3
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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2003 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 14, no 2, 529-544 p.Article in journal (Refereed) Published
Abstract [en]

The inhibitory Smad7, a direct target gene for transforming growth factor-beta (TGF-beta), mediates TGF-beta1-induced apoptosis in several cell types. Herein, we report that apoptosis of human prostate cancer PC-3U cells induced by TGF-beta1 or Smad7 overexpression is caused by a specific activation of the p38 mitogen-activated protein kinase pathway in a TGF-beta-activated kinase 1 (TAK1)- and mitogen-activated protein kinase kinase 3 (MKK3)-dependent manner. Expression of dominant negative p38, dominant negative MKK3, or incubation with the p38 selective inhibitor [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole], prevented TGF-beta1-induced apoptosis. The expression of Smad7 was required for TGF-beta-induced activation of MKK3 and p38 kinases, and endogenous Smad7 was found to interact with phosphorylated p38 in a ligand-dependent manner. Ectopic expression of wild-type TAK1 promoted TGF-beta1-induced phosphorylation of p38 and apoptosis, whereas dominant negative TAK1 reduced TGF-beta1-induced phosphorylation of p38 and apoptosis. Endogenous Smad7 was found to interact with TAK1, and TAK1, MKK3, and p38 were coimmunoprecipitated with Smad7 in transiently transfected COS1 cells. Moreover, ectopically expressed Smad7 enhanced the coimmunoprecipitation of HA-MKK3 and Flag-p38, supporting the notion that Smad7 may act as a scaffolding protein and facilitate TAK1- and MKK3-mediated activation of p38.

Place, publisher, year, edition, pages
The American Society for Cell Biology , 2003. Vol. 14, no 2, 529-544 p.
Keyword [en]
Animals, Apoptosis, Blotting; Western, COS Cells, DNA Fragmentation, DNA-Binding Proteins/*metabolism, Enzyme Activation, Enzyme Inhibitors/pharmacology, Genes; Dominant, Humans, In Situ Nick-End Labeling, MAP Kinase Kinase 3, MAP Kinase Kinase Kinases/*metabolism, Male, Microscopy; Fluorescence, Mitogen-Activated Protein Kinase Kinases/*metabolism, Mitogen-Activated Protein Kinases/*metabolism, Phosphorylation, Precipitin Tests, Prostatic Neoplasms/*pathology, Protein Binding, Protein-Tyrosine Kinase/*metabolism, Research Support; Non-U.S. Gov't, Time Factors, Trans-Activators/*metabolism, Transfection, Transforming Growth Factor beta/metabolism/*physiology, Tumor Cells; Cultured, p38 Mitogen-Activated Protein Kinases
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-90261DOI: 10.1091/mbc.02–03–0037PubMedID: 12589052OAI: oai:DiVA.org:uu-90261DiVA: diva2:162557
Available from: 2003-04-03 Created: 2003-04-03 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Mechanisms for TGF-β-Mediated Regulation of the Actin Filament System and Apoptosis
Open this publication in new window or tab >>Mechanisms for TGF-β-Mediated Regulation of the Actin Filament System and Apoptosis
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transforming growth factor-β (TGF-β) is a member of a large superfamily of cytokines which participate in many different types of cellular processes, such as growth inhibition, cell migration, differentiation, cell adhesion, wound healing and immunosuppression. Alterations of TGF-β superfamily signalling results in several different disorders, including bone disease, vascular disease and cancer. The TGF-β signalling pathways involve several different proteins, such as the Smad proteins, which upon receptor activation are translocated to the nucleus, where they affect transcriptional responses.

The actin cytoskeleton is an organised network of filaments with a highly dynamic structure, which is under a continuous reconstruction to control the morphology, survival, growth and motility of eukaryotic cells. The members of the family of small GTP-binding proteins have been shown to be important regulators of the actin cytoskeleton.

TGF-β was found to induce short term as well as long term actin reorganisation in prostate cancer cells. The short term response included membrane ruffling, and required signalling by the small GTPases Cdc42 and Rho as well as, the involvement of the mitogen-activated protein kinases p38 (p38 MAPK). The long term response included formation of stress fibers and required a cooperation between Smad and Rho GTPase signalling pathways involving the Rho-associated coiled-coil-containing protein kinase 1 (ROCK1).

The TGF-β-induced activation of Cdc42 was, furthermore, shown to require the inhibitory Smad7 and p38 MAP kinase, via a PI3K-dependent pathway. Mixed lineage kinase 3 (MLK3), a mediator downstream of Cdc42, was necessary for the Cdc42-dependent actin filament reorganisation.

Apoptosis is an important and carefully regulated process in human development and disease, which allows the multicellular organisms to remove cells that are in excess or potentially dangerous. TGF-β family members can induce apoptosis in many different cell types, in the presence or absence of other growth factors. Smad7 had previously been shown to be necessary for TGF-β-induced apoptosis of epithelial cells. We could show that Smad7 is required for TGF-β-induced activation of the TGF-β activated kinase 1 (TAK1)-mitogen-activated protein kinase kinase 3 (MKK3)-p38 MAPK pathway, which subsequently leads to apoptosis in prostate cancer cells.

Members of the lymphoid enhancer factor-1/T-cell factor (LEF1/TCF) family of transcription factors have, together with β-catenin, been shown to be nuclear effectors in the Wnt-signalling pathway. We investigated a possible cross-talk between the TGF-β and Wnt signalling pathways. We found that TGF-β, in a Smad7-dependent manner induced a nuclear accumulation of β-catenin and enhanced the transcriptional activity of β-catenin and the induction of the downstream target gene c-myc. Since β-catenin and c-Myc has been shown to promote apoptosis, our results suggests the possibility that β-catenin contributes to TGF-β-induced apoptosis

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 74 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1245
Keyword
Cell and molecular biology, TGF-beta, cytoskeleton, GTPases, mitogen-activated protein kinase kinase 3, TGF-beta-activated kinase 1, Apoptosis, Smad7, beta-catenin, p38 MAPK, Cell- och molekylärbiologi
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Cellbiology
Identifiers
urn:nbn:se:uu:diva-3378 (URN)91-554-5586-7 (ISBN)
Public defence
2003-04-25, B41, Biomedical center (BMC), Uppsala, 13:15
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Supervisors
Available from: 2003-04-03 Created: 2003-04-03Bibliographically approved

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Aspenström, PontusHeuchel, RainerHeldin, Nils-Erikten Dijke, PeterHeldin, Carl-HenrikLandström, Maréne

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