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Simicek M.,Center for the Biology of Disease | Simicek M.,Catholic University of Leuven | Lievens S.,VIB | Lievens S.,Ghent University | And 15 more authors.
Nature Cell Biology | Year: 2013

The RAS-like GTPase RALB mediates cellular responses to nutrient availability or viral infection by respectively engaging two components of the exocyst complex, EXO84 and SEC5. RALB employs SEC5 to trigger innate immunity signalling, whereas RALB-EXO84 interaction induces autophagocytosis. How this differential interaction is achieved molecularly by the RAL GTPase remains unknown. We found that whereas GTP binding turns on RALB activity, ubiquitylation of RALB at Lys 47 tunes its activity towards a particular effector. Specifically, ubiquitylation at Lys 47 sterically inhibits RALB binding to EXO84, while facilitating its interaction with SEC5. Double-stranded RNA promotes RALB ubiquitylation and SEC5-TBK1 complex formation. In contrast, nutrient starvation induces RALB deubiquitylation by accumulation and relocalization of the deubiquitylase USP33 to RALB-positive vesicles. Deubiquitylated RALB promotes the assembly of the RALB-EXO84-beclin-1 complexes driving autophagosome formation. Thus, ubiquitylation within the effector-binding domain provides the switch for the dual functions of RALB in autophagy and innate immune responses. © 2013 Macmillan Publishers Limited. All rights reserved. Source


Lomakina M.E.,Institute of Carcinogenesis
British Journal of Cancer | Year: 2016

Background:The Arp2/3 complex is required for cell migration and invasion. The Arp2/3 complex and its activators, such as the WAVE complex, are deregulated in diverse cancers. Here we investigate the expression of Arpin, the Arp2/3 inhibitory protein that antagonises the WAVE complex.Methods:We used qRT–PCR and reverse phase protein arrays in a patient cohort with known clinical parameters and outcome, immunofluorescence in breast biopsy cryosections and breast cancer cell lines.Results:Arpin was downregulated at the mRNA and protein levels in mammary carcinoma cells. Arpin mRNA downregulation was associated with poor metastasis-free survival (MFS) on univariate analysis (P=0.022). High expression of the NCKAP1 gene that encodes a WAVE complex subunit was also associated with poor MFS on univariate analysis (P=0.0037) and was mutually exclusive with Arpin low. Arpin low or NCKAP1 high was an independent prognosis factor on multivariate analysis (P=0.0012) and was strongly associated with poor MFS (P=0.000064).Conclusions:Loss of the Arp2/3 inhibitory protein Arpin produces a similar poor outcome in breast cancer as high expression of the NCKAP1 subunit of the Arp2/3 activatory WAVE complex.British Journal of Cancer advance online publication, 11 February 2016; doi:10.1038/bjc.2016.18 www.bjcancer.com. © 2016 Cancer Research UK Source


Lichtenstein A.V.,Institute of Carcinogenesis
Biochemistry (Moscow) | Year: 2014

Cancer research has shifted in recent years from studying intracellular processes (identification of damaged genes and signaling pathways) to extracellular (hierarchy of tumor cells, cell transitions, clone competition) and tissue (interactions of a tumor with its environment) research. But then the next step seems to be logical: studying biochemistry of tumor-bearing organisms (namely, cancer-induced changes in cellular and tissue metabolism leading to the organism's death). These data can help to develop new methods of cancer treatment. This article discusses some of the challenges of contemporary oncology and possible ways to overcome them. © 2014 Pleiades Publishing, Ltd. Source


Volkov M.S.,Institute of Carcinogenesis | Kobliakov V.A.,Institute of Carcinogenesis
Tsitologiya | Year: 2011

Effect of carcinogenic polycyclic aromatic hydrocarbons (PAH) benzo(a)pyrene (BP) and 3-methylcholanthrene (MC) on transcription factor NF-kB activation was studied. The determination of NF-kB activity was performed by two different methods: determination of mRNA expression of NF-kB-dependent I-kB gene, and determination of transcription activity of co-transfected with the plasmid containing the luciferase reporter gene under the NF-kB-sensitive promoter. As a subject of inquiry the hepatoma cell cultures HepG2 expressed Ah receptor and G27 not expressed Ah receptor were used. BP and MC weekly enhanced NF-kB activity in proliferating HepG2 cells. The enhance of NF-kB activity was significantly higher in resting cells. NF-kB activation by BP and MC in hepatoma G27 cells was significantly higher in hepatima G27 cells than in HepG2 cells both in proliferating and resting cells. The role of Ah receptor in PAH action on NF-kB activation is discussed. Source


Scherbakov A.M.,Institute of Clinical Oncology | Andreeva O.E.,Institute of Carcinogenesis | Shatskaya V.A.,Institute of Carcinogenesis | Krasil'Nikov M.A.,Institute of Carcinogenesis
Journal of Cellular Biochemistry | Year: 2012

The loss of hormonal dependency of breast tumor cells is often accompanied with the appearance of epithelial-mesenchymal transition (EMT) features and increase in cell metastasis and invasiveness. The central role in the EMT belongs to transcription factors Snail responded for the decrease in E-cadherin expression and cell contacts, stimulation of cell mobility and invasiveness. Aim was to study the relationships between estrogen receptor machinery and Snail1 signaling, and mechanism of Snail1 regulation in hormone-resistant breast cancer cells. The experiments were performed on the estrogen-dependent MCF-7 breast cancer cells, estrogen-hyposensitive MCF-7/LS subline generated through long-term cultivation of the parental cells in steroid-free medium, and ER-negative estrogen-resistant HBL-100 cells. Snail1, estrogen receptor, p65 NF-κB, E-cadherin levels were analyzed by Western blot. We found that decrease in the estrogen dependency is correlated with increase in Snail1 expression and activity, we demonstrated the Snail1 involvement in the negative regulation of ER, and showed that Snail1 inhibition partially restores the sensitivity of the estrogen-hyposensitive cells to antiestrogen tamoxifen. Furthermore, NF-κB was found to serve as a positive regulator of Snail1 in breast cancer cells, and simultaneous inhibition of NF-κB and Snail1 resulted in additional increase in cell response to tamoxifen. In general, the results obtained demonstrate the phenomenon of Snail1 activation in the hormone-resistant breast cancer cells, and show that Snail1 and NF-κB may serve as an important targets in the treatment of breast cancer, both estrogen-dependent and estrogen-independent tumors. © 2012 Wiley Periodicals, Inc. Source

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