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[Cancer Research 62, 5076-5082, September 1, 2002]
© 2002 American Association for Cancer Research

Molecular Biology and Genetics

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

Rizwan Haq, James D. Brenton, Mark Takahashi, Dina Finan, Robert Rottapel and Brent Zanke2

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 p38HOG 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, p38HOG 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 p21CIP, 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 p38HOG as an intracellular pathway that activates a senescence checkpoint in tumor cells and may play a role in Ras- or stress-induced senescence.




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