This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Haq, R. Articles by Zanke, B. Search for Related Content PubMed PubMed Citation Articles by Haq, R. Articles by Zanke, B.

Constitutive p38HOG Mitogen-activated Protein Kinase Activation Induces Permanent Cell Cycle Arrest and Senescence¹

Institute of Medical Science, University of Toronto [R. H., B. Z.]; Ontario Cancer Institute [R. H., J. D. B., M. T., D. F., R. R., B. Z.]; and Department of Medical Oncology and Hematology, Princess Margaret Hospital [J. D. B., B. Z.], Toronto M6G 2M2, Ontario, Canada

Cellular senescence, initially observed during subculturing of normal diploid fibroblasts, can also be induced by chronic exposure to cellular stress, such as UV light, oxidative stress, or DNA damaging agents. Here we demonstrate that stable expression of an activated form of MKK6 (MKK6EE), a direct activator of the stress-induced p38^HOG mitogen-activated protein kinase pathway, is sufficient for inducing features of senescence including a flattened, vacuolated, and irregular morphology, staining for acidic ß-galactosidase, and accumulation of age-associated pigments. Consistent with the senescent phenotype, p38^HOG activation induces a G₁ cell cycle arrest, which is permanent and irreversible after 4 days. MKK6EE also induces biochemical features of senescence in a p38-dependent manner, including enhanced expression of p21^CIP, a cyclin-dependent kinase inhibitor. Microarray analysis of MKK6EE cells showed a pattern of gene expression noted previously in Werner Syndrome and senescent fibroblasts. These results define p38^HOG as an intracellular pathway that activates a senescence checkpoint in tumor cells and may play a role in Ras- or stress-induced senescence.

This article has been cited by other articles:

				A. K. Linnemann and S. A. Krawetz Silencing by nuclear matrix attachment distinguishes cell-type specificity: association with increased proliferation capacity Nucleic Acids Res., May 1, 2009; 37(9): 2779 - 2788. [Abstract] [Full Text] [PDF]

				J. Kwong, L. Hong, R. Liao, Q. Deng, J. Han, and P. Sun p38{alpha} and p38{gamma} Mediate Oncogenic ras-induced Senescence through Differential Mechanisms J. Biol. Chem., April 24, 2009; 284(17): 11237 - 11246. [Abstract] [Full Text] [PDF]

				A. Abrahams, S. Mowla, M. I. Parker, C. R. Goding, and S. Prince UV-mediated Regulation of the Anti-senescence Factor Tbx2 J. Biol. Chem., January 25, 2008; 283(4): 2223 - 2230. [Abstract] [Full Text] [PDF]

				F. Riuzzi, G. Sorci, and R. Donato RAGE Expression in Rhabdomyosarcoma Cells Results in Myogenic Differentiation and Reduced Proliferation, Migration, Invasiveness, and Tumor Growth Am. J. Pathol., September 1, 2007; 171(3): 947 - 961. [Abstract] [Full Text] [PDF]

				X. Zhang, J. Kim, R. Ruthazer, M. A. McDevitt, D. E. Wazer, K. E. Paulson, and A. S. Yee The HBP1 Transcriptional Repressor Participates in RAS-Induced Premature Senescence Mol. Cell. Biol., November 15, 2006; 26(22): 8252 - 8266. [Abstract] [Full Text] [PDF]

				V. Probin, Y. Wang, A. Bai, and D. Zhou Busulfan Selectively Induces Cellular Senescence but Not Apoptosis in WI38 Fibroblasts via a p53-Independent but Extracellular Signal-Regulated Kinase-p38 Mitogen-Activated Protein Kinase-Dependent Mechanism J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 551 - 560. [Abstract] [Full Text] [PDF]

				T. Davis, D. M. Baird, M. F. Haughton, C. J. Jones, and D. Kipling Prevention of Accelerated Cell Aging in Werner Syndrome Using a p38 Mitogen-Activated Protein Kinase Inhibitor J. Gerontol. A Biol. Sci. Med. Sci., November 1, 2005; 60(11): 1386 - 1393. [Abstract] [Full Text] [PDF]

				O. Beyne-Rauzy, N. Prade-Houdellier, C. Demur, C. Recher, J. Ayel, G. Laurent, and V. Mansat-De Mas Tumor necrosis factor-{alpha} inhibits hTERT gene expression in human myeloid normal and leukemic cells Blood, November 1, 2005; 106(9): 3200 - 3205. [Abstract] [Full Text] [PDF]

				H. P. Kim, X. Wang, A. Nakao, S. I. Kim, N. Murase, M. E. Choi, S. W. Ryter, and A. M. K. Choi Caveolin-1 expression by means of p38{beta} mitogen-activated protein kinase mediates the antiproliferative effect of carbon monoxide PNAS, August 9, 2005; 102(32): 11319 - 11324. [Abstract] [Full Text] [PDF]

				R. Kaur, X. Liu, O. Gjoerup, A. Zhang, X. Yuan, S. P. Balk, M. C. Schneider, and M. L. Lu Activation of p21-activated Kinase 6 by MAP Kinase Kinase 6 and p38 MAP Kinase J. Biol. Chem., February 4, 2005; 280(5): 3323 - 3330. [Abstract] [Full Text] [PDF]

				M.-S. Jung, D.-H. Jin, H.-D. Chae, S. Kang, S.-C. Kim, Y.-J. Bang, T.-S. Choi, K.-s. Choi, and D. Y. Shin Bcl-xL and E1B-19K Proteins Inhibit p53-induced Irreversible Growth Arrest and Senescence by Preventing Reactive Oxygen Species-dependent p38 Activation J. Biol. Chem., April 23, 2004; 279(17): 17765 - 17771. [Abstract] [Full Text] [PDF]

				N. N. Gushwa, D. Hayashi, A. Kemper, B. Abram, J. E. Taylor, J. Upton, C. F. Tay, S. Fiedler, S. Pullen, L. P. Miller, et al. Thermotolerant Guard Cell Protoplasts of Tree Tobacco Do Not Require Exogenous Hormones to Survive in Culture and Are Blocked from Reentering the Cell Cycle at the G1-to-S Transition Plant Physiology, August 1, 2003; 132(4): 1925 - 1940. [Abstract] [Full Text] [PDF]

				I. B. Roninson Tumor Cell Senescence in Cancer Treatment Cancer Res., June 1, 2003; 63(11): 2705 - 2715. [Abstract] [Full Text] [PDF]

				J. A. Aguirre-Ghiso, Y. Estrada, D. Liu, and L. Ossowski ERKMAPK Activity as a Determinant of Tumor Growth and Dormancy; Regulation by p38SAPK Cancer Res., April 1, 2003; 63(7): 1684 - 1695. [Abstract] [Full Text] [PDF]