By blocking apoptosis, Bcl-2 in p38-dependent manner promotes cell cycle arrest and accelerated senescence after DNA damage and serum withdrawal.
E1A+ras-transformed rodent fibroblasts are unable to be arrested in the cell cycle and die by apoptosis in response to cytostatics, ionizing radiation (IR), or serum withdrawal. Overexpression of the human antiapoptotic gene bcl-2 suppresses apoptosis and induces reversible cell cycle arrest after IR or serum withdrawal and cell senescence after adriamycin treatment. Bcl-2-sustained adriamycin-induced cell senescence requires p38 MAPK, since the knockout of p38 MAPK abrogated anti-apoptotic and senescence-inducing effects of Bcl-2 in adriamycin-treated cells. Moreover, resistance to apoptosis and cell cycle arrest were not observed in p38-/- E1A+ras+bcl-2-transformants following IR or serum deprivation. However, the pro-apoptotic effect of nocodazole in E1A+ras-transformed cells can not be prevented by Bcl-2 overexpression independently of the presence of p38 MAPK. These results allow us to conclude that p38 is necessary for Bcl-2-induced inhibition of apoptosis, induction of cell cycle arrest and accelerated senescence after DNA damage and serum starvation, but not after nocodazole treatment.
Nelyudova
Anna
A
Laboratory of Molecular Mechanisms of Cell Differentiation, Institute of Cytology, Russian Academy of Sciences, Saint Petersburg, Russia. annanelioudova@hotmail.com
Aksenov
Nikolay
N
Pospelov
Valery
V
Pospelova
Tatiana
T
D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D016922:Cellular Senescence / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D006801:Humans; D015739:Nocodazole / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011839:Radiation, Ionizing; D051381:Rats; D044967:Serum; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins; D015739:Nocodazole