Translocation of SAPK/JNK to mitochondria and interaction with Bcl-x(L) in response to DNA damage.
Activation of the stress-activated protein kinase (SAPK/JNK) by genotoxic agents is necessary for induction of apoptosis. We report here that ionizing radiation ionizing radiation exposure induces translocation of SAPK to mitochondria and association of SAPK with the anti-apoptotic Bcl-x(L) protein. SAPK phosphorylates Bcl-x(L) on threonine 47 (Thr-47) and threonine 115 (Thr-115) in vitro and in vivo. In contrast to wild-type Bcl-x(L), a mutant Bcl-x(L) with the two threonines substituted by alanines (Ala-47, Ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis. These findings indicate that translocation of SAPK to mitochondria is functionally important for interactions with Bcl-x(L) in the apoptotic response to genotoxic stress.
Kharbanda
S
S
Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. surendervkharbanda@dfci.harvard.edu
Saxena
S
S
Yoshida
K
K
Pandey
P
P
Kaneki
M
M
Wang
Q
Q
Cheng
K
K
Chen
Y N
YN
Campbell
A
A
Sudha
T
T
Yuan
Z M
ZM
Narula
J
J
Weichselbaum
R
R
Nalin
C
C
Kufe
D
D
D017209:Apoptosis / Q000502:physiology*; D001692:Biological Transport; D002451:Cell Compartmentation; D004249:DNA Damage / Q000502:physiology*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016296:Mutagenesis; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D011994:Recombinant Proteins / Q000378:metabolism; D020298:U937 Cells; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051020:bcl-X Protein; D020928:Mitogen-Activated Protein Kinases