TGF beta signalling and its role in tumour pathogenesis.

• Authors: Bozena Kaminska , Aleksandra Wesolowska , Malgorzata Danilkiewicz
• Languages of publication: EN

Abstracts

EN

Transforming growth factor beta (TGF-β) is a multifunctional cytokine involved in the regulation of cell proliferation, differentiation and survival/or apoptosis of many cells. Knock-out experiments in mice for the three isoforms of TGF-β have demonstrated their importance in regulating inflammation and tissue repair. TGF-β is implicated in the pathogenesis of human diseases, including tissue fibrosis and carcinogenesis. TGF-β receptors act through multiple intracellular pathways. Upon binding of TGF-β with its receptor, receptor-regulated Smad2/3 proteins become phosphorylated and associate with Smad4. Such complex translocates to the nucleus, binds to DNA and regulates transcription of specific genes. Negative regulation of TGF-β/Smad signalling may occur through the inhibitory Smad6/7. Furthermore, TGF-β-activated kinase-1 (TAK1) is a component of TGF-β signalling and activates stress-activated kinases: p38 through MKK6 or MKK3 and c-Jun N-terminal kinases (JNKs) via MKK4. In the brain TGF-β, normally expressed at the very low level, increases dramatically after injury. Increased mRNA levels of the three TGF-β isoforms correlate with the degree of malignancy of human gliomas. TGF-βs are secreted as latent precursors requiring activation into the mature form. TGF-β may contribute to tumour pathogenesis by direct support of tumour growth and influence on local microenvironment, resulting in immunosuppression, induction of angiogenesis, and modification of the extracellular matrix. TGF-β1,2 may stimulate production of vascular endothelial growth factor (VEGF) as well as plasminogen activator inhibitor (PAI-I), that are involved in vascular remodelling occurring during angiogenesis. Blocking of TGF-β action inhibits tumour viability, migration, metastases in mammary cancer, melanoma and prostate cancer model. Reduction of TGF-β production and activity may be a promising target of therapeutic strategies to control tumour growth.

Keywords

EN

Smad propteins; RNA interference.; TGF beta signal transduction; tumour invasion; cancer therapy; MAP kinases

• Journal: Acta Biochimica Polonica
• Year: 2005
• Volume: 52
• Issue: 2
• Pages: 329-337

Dates

published

2005

received

2005-04-05

revised

2005-05-09

accepted

2005-05-31

Contributors

author

Bozena Kaminska

• Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Warszawa, Poland

author

Aleksandra Wesolowska

• Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Warszawa, Poland

author

Malgorzata Danilkiewicz

• Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Warszawa, Poland

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