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  • Oncogenes induce senescence with incomplete growth arrest and suppress the DNA damage response in immortalized cells.

Oncogenes induce senescence with incomplete growth arrest and suppress the DNA damage response in immortalized cells.

Aging cell (2011-08-10)
Michael Y Sherman, Le Meng, Martha Stampfer, Vladimir L Gabai, Julia A Yaglom
ABSTRACT

Activation of the Her2 (ErbB2) oncogene is implicated in the development of breast, ovary and other cancers. Here, we show that expression of NeuT, a mutant-activated rodent isoform of Her2, in immortalized breast epithelial cells, while promoting senescence-associated morphological changes, up-regulation of senescence-associated β-galactosidase activity, and accumulation of the cyclin-dependent kinase inhibitor p21, failed to trigger the major senescence end-point, i.e. permanent growth arrest. Similar senescence-associated phenotype with incomplete growth arrest, which we dubbed senescence with incomplete growth arrest (SWING), could also be triggered by the expression of the Ras oncogene. SWING phenotype was stable, and persisted in tumor xenografts established from NeuT-transduced cells. Furthermore, a significant population of cells in SWING state was found in tumors in the MMTV/NeuT transgenic mouse model. SWING cells showed downregulation of histone H2AX, critical for repair of double-stranded DNA breaks, and impaired activation of Chk1 kinase. Overall, SWING cells were characterized by increased DNA instability and hypersensitivity to genotoxic stresses. We propose that the SWING state could be a stage in the process of cancer development.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-phospho-Histone H2A.X (Ser139) Antibody, clone JBW301, clone JBW301, Upstate®, from mouse