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Sustained TGF beta ...
Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis
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- Gal, Annamaria (författare)
- Uppsala universitet,Ludwiginstitutet för cancerforskning
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- Sjöblom, Tobias (författare)
- Uppsala universitet,Ludwiginstitutet för cancerforskning
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- Fedorova, L. (författare)
- Microbiology and Tumour Biology Center, Karolinska Institute, Stockholm, Sweden
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- Imreh, S. (författare)
- Karolinska Institutet
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- Beug, Hartmut (författare)
- Research Institute of Molecular Pathology, Vienna, Austria
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- Moustakas, Aristidis (författare)
- Uppsala universitet,Ludwiginstitutet för cancerforskning
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(creator_code:org_t)
- 2007-08-27
- 2008
- Engelska.
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 27:9, s. 1218-1230
- Relaterad länk:
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https://www.nature.c...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- To better understand the dual, tumour-suppressive and tumour-promoting function of transforming growth factor-beta (TGFbeta), we analysed mammary epithelial NMuMG cells in response to short and long-term TGFbeta exposure. NMuMG cells became proliferation-arrested and apoptotic after exposure to TGFbeta for 2-5 days, whereas surviving cells underwent epithelial-mesenchymal transition (EMT). After chronic TGFbeta exposure (2-3 weeks), however, NMuMG cells became resistant to proliferation arrest and apoptosis, showing sustained EMT instead (TD cells). EMT was fully reversed by a pharmacologic TGFbeta-receptor-I kinase inhibitor or withdrawal of TGFbeta for 6-12 days. Interestingly, both cell cycle arresting/proapoptotic (Smads, p38 kinase) and antiapoptotic, proliferation and EMT-promoting signalling pathways (PI3K-PKB/Akt, ERK) were co-suppressed to low, but significant levels. Except for PI3K-Akt, TGFbeta-dependent downregulation of these signalling pathways in transdifferentiated (TD) cells was fully reversed upon TGFbeta withdrawal, together with partial re-induction of proliferation arrest and apoptosis. Co-injection of non-tumorigenic NMuMG cells with tumour-forming CHO cells oversecreting exogenous TGFbeta1 (CHO-TGFbeta1) allowed outgrowth of epithelioid cells in CHO-TGFbeta1 cell-induced tumours. These epithelial islands enhanced CHO-TGFbeta1 tumour cell proliferation, possibly due to chemokines (for example, JE/MCP-1) secreted by NMuMG/TD cells. We conclude that suppression of antiproliferative, proapoptotic TGFbeta signalling in TD cells may permit TGFbeta-dependent proliferation, survival and EMT-enhancing signalling pathways to act at low levels. Thus, TGFbeta may modulate its own signalling to facilitate switching from tumour suppression to tumour progression.
Nyckelord
- epithelial–mesenchymal transition
- metastasis
- Smad
- signal transduction
- TGFb
- tumour suppression
- MEDICINE
- MEDICIN
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- art (ämneskategori)
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Oncogene
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