title: Defective nuclear translocation of stress-activated signaling in senescent diploid human fibroblasts: a possible explanation for aging-associated apoptosis resistance.
abstract: In order to study the nature of aging-dependent apoptosis resistance, we compared the activation pattern of mitogen-activated protein kinases (MAPK) in response to three different stress modalities: hydrogen peroxide (H(2)O(2)), staurosporine, and thapsigargin. We observed the agonist-specific activation pattern of MAP kinases in human diploid fibroblasts (HDFs). When young HDFs were treated with PD98059, a specific inhibitor of extracellular signal-regulated kinase (ERK), H(2)O(2)-induced apoptosis was blocked, whereas staurosporine-induced apoptosis was inhibited by treatment with SB203580, a specific inhibitor of p38. In addition, the levels of anti-apoptotic protein Bcl-2 (B-cell lymphoma protein-2) were restored by PD98059 or SB239063 in cells treated with H(2)O(2) or staurosporine, respectively. We also found that inhibition of the nuclear import of p-Erk and p-p38 using wheat germ agglutinin induced apoptosis resistance in young HDF cells in response to H(2)O(2) or staurosporine. These data indicate a potential role of the nuclear translocation of apoptotic signals in the induction of apoptosis. Moreover, the nuclear translocation of activated ERK1/2 and p38 in response to H(2)O(2) or staurosporine was significantly compromised in senescent HDFs, compared with young cells. Taken together, we propose that the apoptosis resistance of senescent HDFs might be related to the defective nuclear translocation of stress-activated signals in an agonist-specific manner, which would imply the operation of an aging-dependent functional nucleo-cytoplasmic trafficking barrier.
authors.affiliation: Department of Biochemistry and Molecular Biology, Aging and Apoptosis Research Center, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: Sung Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Ryu
authors.forename: Hyun Tae
authors.initials: HT
authors.lastname: Kang
authors.forename: Hae Ri
authors.initials: HR
authors.lastname: Choi
authors.forename: Sang Chul
authors.initials: SC
authors.lastname: Park
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D018929:Cell Culture Techniques; D002470:Cell Survival; D002478:Cells, Cultured; D016922:Cellular Senescence; D002675:Child, Preschool; D004171:Diploidy; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D052816:Foreskin / Q000166:cytology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007399:Interphase; D020935:MAP Kinase Signaling System; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D013312:Stress, Physiological; D014909:Wheat Germ Agglutinins / Q000494:pharmacology
chemical_list: D005419:Flavonoids; D007093:Imidazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D014909:Wheat Germ Agglutinins; D006861:Hydrogen Peroxide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020928:Mitogen-Activated Protein Kinases; D019311:Staurosporine; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one