Phosphorylation of ezrin by cyclin-dependent kinase 5 induces the release of Rho GDP dissociation inhibitor to inhibit Rac1 activity in senescent cells.
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.
Yang
Hi-Su
HS
Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111, USA.
Hinds
Philip W
PW
D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D000099149:Ezrin
D051360:Cyclin-Dependent Kinase 5; D003598:Cytoskeletal Proteins; D020730:Guanine Nucleotide Dissociation Inhibitors; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D020830:rac1 GTP-Binding Protein; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D000099149:Ezrin; C107953:RAC1 protein, human