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Cancer Res ; 66(5): 2708-15, 2006 Mar 01.
Article in English | MEDLINE | ID: mdl-16510591

ABSTRACT

Normal somatic cells enter a state of irreversible proliferation arrest-designated cellular senescence, which is characterized by biochemical changes and a distinctive morphology. Cellular stresses, including oncogene activation, can lead to senescence. Consistent with an antioncogenic role in this process, the tumor suppressor pRb plays a critical role in senescence. Reexpression of pRb in human tumor cells results in senescence-like changes, including cell cycle exit and cell shape alteration. Here, we show that pRb-induced senescent SAOS-2 cells and senescent human diploid fibroblasts are accompanied by increased phosphorylation of ezrin at T235 by cyclin-dependent kinase 5 and consequent dissociation of Rho GDP dissociation inhibitor (Rho-GDI) from an ezrin/Rho-GDI complex. The release of Rho-GDI results in increased interaction with Rac1 GTPase and inhibition of Rac1 GTPase activity. In addition, reduction of Rho-GDI by small interfering RNA in pRb-transfected cells prevented senescence-associated flat cell formation, suggesting that Rho-GDI plays an important role in contributing to cellular morphology in the process of senescence.


Subject(s)
Cyclin-Dependent Kinase 5/metabolism , Cytoskeletal Proteins/metabolism , Guanine Nucleotide Dissociation Inhibitors/metabolism , rac1 GTP-Binding Protein/antagonists & inhibitors , Bone Neoplasms/genetics , Bone Neoplasms/metabolism , Bone Neoplasms/pathology , Cell Line, Tumor , Cellular Senescence/physiology , Fibroblasts/cytology , Fibroblasts/metabolism , Guanine Nucleotide Dissociation Inhibitors/biosynthesis , Guanine Nucleotide Dissociation Inhibitors/genetics , Humans , Osteosarcoma/genetics , Osteosarcoma/metabolism , Osteosarcoma/pathology , Phosphorylation , RNA, Small Interfering/genetics , Retinoblastoma Protein/genetics , Retinoblastoma Protein/metabolism , Transfection , rac1 GTP-Binding Protein/metabolism , rho-Specific Guanine Nucleotide Dissociation Inhibitors
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