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المؤلفون: Ohshiro, Kazufumi, Rayala, Suresh K, Wigerup, Caroline, Pakala, Suresh B, Natha, Reddy S Divijendra, Gururaj, Anupama E, Molli, Poonam R, Månsson, Sofie Svensson, Ramezani, Ali, Hawley, Robert G, Landberg, Göran, 1963, Lee, Norman H, Kumar, Rakesh
المصدر: EMBO reports. 11(9):691-7
مصطلحات موضوعية: Cell and Molecular Biology, Cell- och molekylärbiologi, Acetylation, Animals, Cell Line, Cell Movement, Cell Transformation, Neoplastic, Female, Fibroblasts, cytology, physiology, GTP-Binding Protein alpha Subunit, Gi2, genetics, metabolism, Gene Expression Regulation, Histone Deacetylases, Humans, Lysine, Mice, Nude, Neoplasms, Experimental, Oncogenes, Repressor Proteins, Transcription, Genetic, Transplantation, Heterologous, ras Proteins
الوصف: High expression of metastasis-associated protein 1 co-regulator (MTA1), a component of the nuclear remodelling and histone deacetylase complex, has been associated with human tumours. However, the precise role of MTA1 in tumorigenesis remains unknown. In this study, we show that induced levels of MTA1 are sufficient to transform Rat1 fibroblasts and that the transforming potential of MTA1 is dependent on its acetylation at Lys626. Underlying mechanisms of MTA1-mediated transformation include activation of the Ras-Raf pathway by MTA1 but not by acetylation-inactive MTA1; this was due to the repression of Galphai2 transcription, which negatively influences Ras activation. We observed that acetylated MTA1-histone deacetylase (HDAC) interaction was required for the recruitment of the MTA1-HDAC complex to the Galphai2 regulatory element and consequently for the repression of Galphai2 transcription and expression leading to activation of the Ras-Raf pathway. The findings presented in this study provide for the first time--to the best of our knowledge--evidence of acetylation-dependent oncogenic activity of a cancer-relevant gene product.
الوصول الحر: https://gup.ub.gu.se/publication/150800Test
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2دورية أكاديمية
المؤلفون: Ohshiro, Kazufumi, Bui-Nguyen, Tri M., Natha, Reddy S. Divijendra, Schwartz, Arnold M., Levine, Paul, Kumar, Rakesh
المصدر: The International Journal of Biological Markers ; volume 27, issue 4, page 305-313 ; ISSN 1724-6008 1724-6008
الوصف: Inflammatory breast cancer (IBC) accounts for a small fraction but aggressive form of epithelial breast cancer. Although the role of thrombin in cancer is beginning to be unfolded, its impact on the biology of IBC remains unknown. The purpose of this study was to establish the role of thrombin on the invasiveness of IBC cells. The IBC SUM149 cell line was treated with thrombin in the absence or presence of the epidermal growth factor receptor (EGFR) inhibitor erlotinib and protease-activated receptor 1 (PAR1) inhibitor. The effects of pharmacological inhibitors on the ability of thrombin to stimulate the growth rate and invasiveness were examined. We found that the inhibition of putative cellular targets of thrombin action suppresses both the growth and invasiveness of SUM149 cells in a concentration-dependent manner. In addition, thrombin-mediated increased invasion of SUM149 cells was routed through EGFR phosphorylation, and in turn, stimulation of the p21-activated kinase (Pak1) activity in a EGFR-sensitive manner. Interestingly, thrombin-mediated activation of the Pak1 pathway stimulation was blocked by erlotinib and PAR1 inhibitor. For proof-of-principle studies, we found immunohistochemical evidence of Pak1 activation as well as expression of PAR1 in IBC. Thrombin utilizes EGFR to relay signals promoting SUM149 cell growth and invasion via the Pak1 pathway. The study provides the rationale for future therapeutic approaches in mitigating the invasive nature of IBC by targeting Pak1 and/or EGFR.
