Increased activity of the Src tyrosine protein kinase that has been observed in a large number of human malignancies appears to be a promising target for drug therapy. In the present study, a critical role of the Src activity in the deregulation of mTOR signaling pathway in Rous sarcoma virus (RSV)-transformed hamster fibroblasts, H19 cells, was shown using these cells treated with the Src-specific inhibitor, SU6656, and clones of fibroblasts expressing either the active Src or the dominant-negative Src kinase-dead mutant. Disruption of the Src kinase activity results in substantial reduction of the phosphorylation and activity of the Akt/protein kinase B (PKB), phosphorylation of tuberin (TSC2), mammalian target of rapamycin (mTOR), S6K1, ribosomal protein S6, and eukaryotic initiation factor 4E-binding protein 4E-BP1. The ectopic, active Akt1 that was expressed in Src-deficient cells significantly enhanced phosphorylation of TSC2 in these cells, but it failed to activate the inhibited components of the mTOR pathway that are downstream of TSC2. The data indicate that the Src kinase activity is essential for the activity of mTOR-dependent signaling pathway and suggest that mTOR targets may be controlled by Src independently of Akt1/TSC2 cascade in cells expressing hyperactive Src protein. These observations might have an implication in drug resistance to mTOR inhibitor-based cancer therapy in certain cell types.
- MeSH
- Adenoviridae genetika MeSH
- buněčné linie MeSH
- financování organizované MeSH
- fosforylace MeSH
- indoly farmakologie MeSH
- inhibitory proteinkinas farmakologie MeSH
- křečci praví MeSH
- proteinkinasy metabolismus MeSH
- signální transdukce MeSH
- sulfonamidy farmakologie MeSH
- transformované buněčné linie MeSH
- virus Rousova sarkomu genetika MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- zvířata MeSH
beta-catenin has a dual function; it is implicated in intercellular junctions and transcriptional co-activation. Here we examined the regulation of the expression and localization of beta-catenin in HT29 colorectal adenocarcinoma cells. Our results showed that inhibition of PI-3 kinase with wortmannin was accompanied by a considerably reduced expression of beta-catenin. This effect was overcome by butyrate and occurred at the protein level, not at the level of mRNA. Moreover, NaBT significantly increased the phosphorylation of the ribosomal protein, S6, known to participate in the translational control of gene expression. This was accompanied by the increased phosphorylation of p70 S6K and MAPKs, the effector proteins that are upstream of protein S6 in the distinct signaling pathways. These facts indicate that different signaling pathways may be involved in the regulation of beta-catenin synthesis. Modulation of beta-catenin expression induced by NaBT appeared to occur at the level of protein translation, suggesting that NaBT may act as a translational regulator.
- MeSH
- adenokarcinom metabolismus MeSH
- alkalická fosfatasa metabolismus MeSH
- androstadieny metabolismus MeSH
- beta-katenin genetika metabolismus MeSH
- butyráty metabolismus MeSH
- financování organizované MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- fosforylace MeSH
- imunohistochemie MeSH
- inhibitory fosfoinositid-3-kinasy MeSH
- kinasy ribozomálního proteinu S6, 70-kDa metabolismus MeSH
- kinasy ribozomálního proteinu S6 metabolismus MeSH
- kolorektální nádory metabolismus MeSH
- lidé MeSH
- mitogenem aktivované proteinkinasy metabolismus MeSH
- nádorové buněčné linie MeSH
- serin metabolismus MeSH
- signální transdukce fyziologie MeSH
- tyrosin metabolismus MeSH
- Check Tag
- lidé MeSH
- MeSH
- antitumorózní látky terapeutické užití MeSH
- financování organizované MeSH
- genetické jevy genetika imunologie MeSH
- klinické zkoušky, fáze III jako téma MeSH
- lékařská onkologie metody trendy MeSH
- lidé MeSH
- onkogenní proteiny genetika MeSH
- proteinkinasy genetika MeSH
- regulace genové exprese u nádorů genetika imunologie MeSH
- ribozomální protein S6 genetika MeSH
- sirolimus analogy a deriváty farmakologie terapeutické užití MeSH
- skupina kinas odvozených od src-genu genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- abstrakt z konference MeSH
The presence of angiotensin II receptors was found on cells of three colorectal carcinoma cell lines. The binding assays with 125I-labelled angiotensin II and ligands specific for angiotensin AT1 or AT2 receptors showed that angiotensin receptors on colorectal cancer cells are mostly of the AT2 type. The binding capacity of tumor cells was not significantly changed by butyrate-induced differentiation.
- MeSH
- angiotensin II chemie metabolismus MeSH
- blokátory receptoru 1 pro angiotenzin II metabolismus MeSH
- buněčná membrána metabolismus MeSH
- financování organizované MeSH
- kolorektální nádory metabolismus MeSH
- lidé MeSH
- losartan metabolismus MeSH
- nádorové buněčné linie metabolismus MeSH
- oligopeptidy metabolismus MeSH
- radioizotopy jodu metabolismus MeSH
- receptor angiotensinu typ 2 genetika metabolismus MeSH
- Check Tag
- lidé MeSH
