Senescent human diploid fibroblasts undergo a caspase-independent apoptotic death.
Item
-
Title
-
Senescent human diploid fibroblasts undergo a caspase-independent apoptotic death.
-
Identifier
-
AAI3245082
-
identifier
-
3245082
-
Creator
-
Davis, Claudette Patricia.
-
Contributor
-
Adviser: Karen Hubbard
-
Date
-
2007
-
Language
-
English
-
Publisher
-
City University of New York.
-
Subject
-
Biology, Cell | Biology, Molecular
-
Abstract
-
Apoptosis functions to maintain a homeostatic environment within an organism and the slightest disruption in the pathway can trigger the onset of diseases such as cancer and Alzheimer's. Many researchers have made tremendous contributions to the field by deciphering the relevant components of this process. As the elderly are most susceptible to disease, understanding the cause of this vulnerability is important. To study changes associated with aging, we use human diploid fibroblasts as our model system. These fibroblasts cease division after 60-70 +/- 10 population doublings (depending on cell type).;As apoptosis occurs in many experimental systems, senescent fibro blasts were considered resistant to apoptotic death. We previously provided evidence against the aforementioned finding, in that senescent WI38 fibroblasts when challenged with okadaic acid underwent apoptosis. In light of our previous results, a series of experiments were performed to determine the molecular apoptotic pathway used by senescent fibroblasts in the presence of okadaic acid.;A novel pathway has been discovered in that senescent fibroblasts, in response to okadaic acid, go through a caspase-independent death. Interestingly, in the absence of caspase activation, we see down-regulation of a caspase substrate DNA Fragmentation Factor 45 in senescent cells challenged with okadaic acid. In a search for proteins which cause apoptosis in a caspase-independent manner, Apoptosis Inducing Factor was released from the mitochondria and translocated to the nucleus.;Upon closer examination of the mitochondria, we find they become less clustered in senescent cells 24 hours after the addition of okadaic acid. Furthermore, a mitochondrial fission protein, Drp1, binds to these fragments along with Bak. When mitochondrial membrane potential was analyzed, we see elevated levels in young cells, but the potential in senescent cells decreases as early as 6 hours after the addition of okadaic acid.;In view of our findings, it is evident that senescent cells are capable of undergoing an apoptotic death and this death is regulated in a caspase-independent manner. Our results will aide in our understanding of senescent cell death.
-
Type
-
dissertation
-
Source
-
PQT Legacy CUNY.xlsx
-
degree
-
Ph.D.
