TY - JOUR
T1 - Senescent fibroblasts resist apoptosis by downregulating caspase-3
AU - Marcotte, Richard
AU - Lacelle, Chantale
AU - Wang, Eugenia
N1 - Funding Information:
The Authors wish to express their sincere gratitude for the proof-reading and editing work of Mr. Alan N. Bloch. This work was supported by grant R37 AG07444 to EW from the National Institute on Aging of the National Institutes of Health.
PY - 2004/10
Y1 - 2004/10
N2 - In replicative senescence, cells undergo permanent exit from cell cycle traverse; this is traditionally thought to occur at the end of a culture's in vitro life span, after serial passaging. In general, the checkpoint for replicative senescence is found at the G 1/S border, controlled by the modulation of a battery of proteins, typified by gaining inhibitors of cell cycle traverse, such as cyclin-dependent kinases or RB hyperphosphorylation, and losing pro-proliferation gene expressions such as c-fos, c-myc, and a cadre of proliferation-dependent kinases. Here, we present evidence that replicatively senescent fibroblasts are resistant to apoptotic death, associated with a lack of key enzyme activities, caspase-3 being the chief executioner. This observation, coupled with our earlier report that senescent fibroblasts maintain persistently high levels of pro-survival factor Bcl-2, suggests that the molecular signaling program present in fibroblasts at the end of their in vitro life span may not only cater to the state of permanent exit from cell cycle traverse, but also dictate an inability to commit cellular suicide. Future experiments will reveal whether replicatively senescent fibroblasts that can neither proliferate nor die contribute to organismic aging, and whether their accumulation over time in tissue becomes detrimental to the normal aging process.
AB - In replicative senescence, cells undergo permanent exit from cell cycle traverse; this is traditionally thought to occur at the end of a culture's in vitro life span, after serial passaging. In general, the checkpoint for replicative senescence is found at the G 1/S border, controlled by the modulation of a battery of proteins, typified by gaining inhibitors of cell cycle traverse, such as cyclin-dependent kinases or RB hyperphosphorylation, and losing pro-proliferation gene expressions such as c-fos, c-myc, and a cadre of proliferation-dependent kinases. Here, we present evidence that replicatively senescent fibroblasts are resistant to apoptotic death, associated with a lack of key enzyme activities, caspase-3 being the chief executioner. This observation, coupled with our earlier report that senescent fibroblasts maintain persistently high levels of pro-survival factor Bcl-2, suggests that the molecular signaling program present in fibroblasts at the end of their in vitro life span may not only cater to the state of permanent exit from cell cycle traverse, but also dictate an inability to commit cellular suicide. Future experiments will reveal whether replicatively senescent fibroblasts that can neither proliferate nor die contribute to organismic aging, and whether their accumulation over time in tissue becomes detrimental to the normal aging process.
KW - Microarray
KW - Population doubling level
KW - RT-PCR
KW - Replicative senescence
KW - Staurosporine
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U2 - 10.1016/j.mad.2004.07.007
DO - 10.1016/j.mad.2004.07.007
M3 - Article
C2 - 15541772
AN - SCOPUS:8344230643
SN - 0047-6374
VL - 125
SP - 777
EP - 783
JO - Mechanisms of Ageing and Development
JF - Mechanisms of Ageing and Development
IS - 10-11 SPEC. ISS.
ER -