Role for Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis.
Cytochrome C is a mitochondrial protein that induces apoptosis when released into the cytosol or when added to cell-free extracts. Here we show that cells that overexpress the Bcl-2-related protein Bcl-xL fail to accumulate cytosolic cytochrome C or undergo apoptosis in response to genotoxic stress. Coimmunoprecipitation studies demonstrate that Bcl-xL associates with cytochrome C. Cytochrome C binds directly and specifically to Bcl-xL and not to the proapoptotic Bcl-xs protein. The results also demonstrate that Bcl-xs blocks binding of cytochrome C to Bcl-xL. Our findings support a role for Bcl-xL in protecting cells from apoptosis by inhibiting the availability of cytochrome C in the cytosol.
Kharbanda
S
S
Division of Cancer Pharmacology, Dana Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Pandey
P
P
Schofield
L
L
Israels
S
S
Roncinske
R
R
Yoshida
K
K
Bharti
A
A
Yuan
Z M
ZM
Saxena
S
S
Weichselbaum
R
R
Nalin
C
C
Kufe
D
D
D017209:Apoptosis / Q000235:genetics*; D003574:Cytochrome c Group / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein