Constitutive p38HOG mitogen-activated protein kinase activation induces permanent cell cycle arrest and senescence.
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 beta-galactosidase, and accumulation of age-associated pigments. Consistent with the senescent phenotype, p38(HOG) activation induces a G(1) 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.
Institute of Medical Science, University of Toronto, Ontario, Canada.
Rizwan
R
Haq
James D
JD
Brenton
Mark
M
Takahashi
Dina
D
Finan
Ariel
A
Finkielsztein
Sambasivarao
S
Damaraju
Robert
R
Rottapel
Brent
B
Zanke
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology*; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048669:MAP Kinase Kinase 6; D020935:MAP Kinase Signaling System / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D012516:Osteosarcoma / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases