Morphological adjustment of senescent cells by modulating caveolin-1 status.
Morphological change is one of the cardinal features of the senescent phenotype; for example, senescent human diploid cells have a flat large shape. However, the mechanisms underlying such senescence-related morphological alterations have not been well studied. To investigate this situation, we characterized the senescence-dependent changes of cellular structural determinants in terms of their levels and activities. These determinants included integrins, focal adhesion complexes, and small Rho GTPases, and special emphasis was placed on their relationships with caveolin-1 status. We observed that the expression integrin beta(1) and focal adhesion kinase (FAK) were increased and that the phosphorylations of FAK and paxillin, hallmarks of focal adhesion formation, were also increased in senescent human diploid fibroblast cells. Moreover, the Rho GTPases Rac1 and Cdc42 were found to be highly activated in senescent cells. In addition, focal adhesion complexes and Rho GTPases were up-regulated in the caveolin-rich membrane domain in the senescent cells. Activated Rac1 and Cdc42 directly interacted with caveolin-1 in senescent cells. Interestingly, caveolin-1 knock-out senescent cells, achieved by using small interfering RNA and antisense oligonucleotide, showed disrupted focal adhesion formation and actin stress fibers via the inactivation of FAK, which resulted in morphological adjustment to the young cell-like small spindle shape. Based on the results obtained, we propose that caveolin-1 plays an important role in senescence-associated morphological changes by regulating focal adhesion kinase activity and actin stress fiber formation in the senescent cells.
Cho
Kyung A
KA
Department of Biochemistry and Molecular Biology, Aging and Apoptosis Research Center, National University College of Medicine, Seoul, Korea.
Ryu
Sung Jin
SJ
Oh
Yoon Sin
YS
Park
Ji Hyeun
JH
Lee
Jung Weon
JW
Kim
Hwang-Phill
HP
Kim
Kyung Tae
KT
Jang
Ik Soon
IS
Park
Sang Chul
SC
D051242:Caveolin 1; D022461:Caveolins / Q000378:metabolism* / Q000502:physiology; D048429:Cell Size; D002478:Cells, Cultured; D016922:Cellular Senescence; D005347:Fibroblasts / Q000166:cytology*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D022001:Focal Adhesions; D006801:Humans; D019012:Integrin beta1 / Q000032:analysis; D016023:Integrins / Q000032:analysis; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D020764:cdc42 GTP-Binding Protein / Q000032:analysis / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000032:analysis / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000032:analysis
C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D019012:Integrin beta1; D016023:Integrins; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins