c-Abl is a nonreceptor tyrosine kinase that is activated by certain DNA-damaging agents. Recent studies have demonstrated that c-Abl functions upstream of the stress-activated protein kinase (SAPK, JNK) and the p38(MAPK) mitogen-activated protein kinase (p38 MAPK). Other work has shown that DNA damage induces binding of c-Abl to p53 and that c-Abl regulates the G1 growth arrest response to genotoxic stress by a p53-dependent, p21-independent mechanism. Phosphorylation of c-Abl at multiple sites by p34cdc2 during mitosis has also supported a role for this protein tyrosine kinase in G2 phase. Because DNA damage is associated with arrest of cells in G1 and G2 phases, c-Abl activation may play a role in regulating these responses and in stress pathways that include SAPK and p38(MAPK) MAPK. The mechanism responsible for the activation of c-Abl by genotoxic stress are unknown. The proposed work will explore the applicant's recent finding that c-Abl forms a nuclear complex with the DNA-dependent protein kinase (DNA-PK). DNA-PK has been implicated in nuclear processes including transcription, DNA replication, and double-stranded DNA break repair. The Ku autoantigen, a DNA end-binding protein necessary for DNA-PK catalytic activity, recruits DNA-PK to DNA. The applicant's preliminary findings demonstrate that DNA damage induces the formation of a complex of c-Abl with DNA-PK and Ku. This complex also includes the redox protein Ref-1. The applicant's hypothesis is that this nuclear complex contributes to the activation of c-Abl and that c-Abl regulates the induction of DNA-PK activity by associating with Ku. The findings obtained in the proposed work should represent a paradigm for studies on early events in the cellular response to genotoxic stress.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA075216-01
Application #
2382799
Study Section
Biochemistry Study Section (BIO)
Project Start
1997-08-05
Project End
2000-07-31
Budget Start
1997-08-05
Budget End
1998-07-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
Ito, Y; Pandey, P; Sathyanarayana, P et al. (2001) Interaction of hematopoietic progenitor kinase 1 and c-Abl tyrosine kinase in response to genotoxic stress. J Biol Chem 276:18130-8
Kumar, V; Sabatini, D; Pandey, P et al. (2000) Regulation of the rapamycin and FKBP-target 1/mammalian target of rapamycin and cap-dependent initiation of translation by the c-Abl protein-tyrosine kinase. J Biol Chem 275:10779-87
Pandey, P; Saleh, A; Nakazawa, A et al. (2000) Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J 19:4310-22
Chauhan, D; Pandey, P; Hideshima, T et al. (2000) SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells. J Biol Chem 275:27845-50
Kharbanda, S; Kumar, V; Dhar, S et al. (2000) Regulation of the hTERT telomerase catalytic subunit by the c-Abl tyrosine kinase. Curr Biol 10:568-75
Kharbanda, S; Saxena, S; Yoshida, K et al. (2000) Translocation of SAPK/JNK to mitochondria and interaction with Bcl-x(L) in response to DNA damage. J Biol Chem 275:322-7
Yoshida, K; Weichselbaum, R; Kharbanda, S et al. (2000) Role for Lyn tyrosine kinase as a regulator of stress-activated protein kinase activity in response to DNA damage. Mol Cell Biol 20:5370-80
Pandey, P; Farber, R; Nakazawa, A et al. (2000) Hsp27 functions as a negative regulator of cytochrome c-dependent activation of procaspase-3. Oncogene 19:1975-81
Kharbanda, S; Pandey, P; Yamauchi, T et al. (2000) Activation of MEK kinase 1 by the c-Abl protein tyrosine kinase in response to DNA damage. Mol Cell Biol 20:4979-89
Kumar, V; Pandey, P; Sabatini, D et al. (2000) Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of translation. EMBO J 19:1087-97

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