The role of the MEK/ERK pathway in regulation of HDACI-induced senescence of transformed rat embryo fibroblasts
- 47 Downloads
A key regulator of cellular senescence, mTORC1 complex, is a target of many signaling cascades, including Ras/Raf/MEK/ERK cascade. In this paper, we investigated the role of the MEK/ERK branch of this cascade in the process of cellular senescence induced by sodium butyrate (NaBut), a histone deacetylase inhibitor (HDACI), in transformed rat-embryo fibroblasts. Suppression of MEK/ERK activity by inhibitor PD0325901 did not prevent activation of mTORC1 complex induced by NaBut treatment. Inhibition of MEK/ERK increased mTORC1 activity and activated mTORC2 complex. Activation of mTOR-containing complexes was accompanied by reorganization of the actin cytoskeleton (formation of actin stress fibers) and the appearance of cellular senescence markers. In contrast to NaBut-induced senescence, no protein accumulation was observed, probably due to increased activity of the degradation processes. Furthermore, senescence induction under suppression of MEK/ERK drastically decreased the cell viability, Thus, NaBut-induced senescence upon suppressed activity of the MEK/ERK branch of MAP kinase cascade has a more pronounced tumor-suppressing effect that is manifested by activation of both mTOR complexes, reorganization of the actin cytoskeleton and protein degradation.
Keywordsinhibitor of histone deacetylases sodium butyrate senescence-associated β-galactosidase
histone deacetylase inhibitor
Unable to display preview. Download preview PDF.
- Bîs, J.L., Ras oncogenes in human cancer: a review, Cancer Res., 1989, vol. 49, pp. 4682–4689.Google Scholar
- Deschenez-Simard, X., Gamount-Leclerc, M.-F., Bourdeau, V., Lessard, F., Moiseeva, O., Forest, V., Igelmann, S., Mallette, F.A., Saba-El-Leil, M.K., Meloche, S., Saad, F., Mes-Masson, A.M., and Ferbeyre, G., Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation, Genes Dev., 2013, vol. 27, pp. 900–915.CrossRefGoogle Scholar
- Dimri, J.P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E.E., Linskens, M., Rubelj, I., Pereira-Smith, O., Peacocke, M., and Campisi, J., A Biomarker that identifies senescent human cells in culture and in aging skin in vivo, Proc. Nat. Acad. Sci. USA., 1995, vol. 95, pp. 10541–10546.Google Scholar
- Guo, G.Y., Chen, H.-Y., Mathew, R., Fan. J., Strohecker, A.M., Karsli-Uzunbas, G., Kamphorst, J.J., Chen, G., Lemons, J.M.L., Karantza, V., Coller, H.A., DiPaola, R.S., Gelinas, S., Rabinowitz, J.D., and White, E., Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis, Genes Dev., 2010, vol. 25, pp. 460–470.CrossRefGoogle Scholar
- Moreno-Lauseca, P. and Streuli, C.H., Signalling pathways linking integrins with cell cycle progression, Matrix Biol., 2013. doi: 10.1016/j.matbio.2013.10.011Google Scholar
- Romanov, V.S., Abramova, M.V., Svetlikova, S.B., Bykova, T.V., Zubova, S.G., Aksenov, N.D., Fornace, A.J.Jr., Pospelova, T.V., and Pospelov, V.A., P21waf1 is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate, Cell Cycle, 2010, vol. 9, pp. 1–11.CrossRefGoogle Scholar
- Shapiro, H.M., Practical Flow Cytometry, New York: Alan R. Liss, Inc., 1988.Google Scholar
- Wu, X.-N., Wang, X.-K., Wu, S.-Q., Lu, J., Zheng, M., Wang, Y.-H., Zhou, H., Zhang, H., and Han, J., Phosphorylation of raptor by p38 participates in arsenite-induced mammalian target of rapamycin complex 1 (mTORC1) activation, J. Biol. Chem., 2011, vol. 286, pp. 31501–31511.PubMedCrossRefPubMedCentralGoogle Scholar
- Zubova, Yu.G., Bykova, T.V., Zubova, S.G., Abramova, M.V., Aksenov, N.D., Pospelov, V.A., and Pospelova, T.V., Induction of premature senescence program by an inhibitor of histone deacetylase sodium butyrate in normal and transformed rat fibroblasts, Tsitologiia, 2005, vol. 47, no. 12, pp. 1055–1062.PubMedGoogle Scholar