ATM Is Required for I
B Kinase (IKK) Activation in
Response to DNA Double Strand Breaks*
Nanxin
Li
,
Sharon
Banin§,
Honghai
Ouyang¶,
Gloria C.
Li¶,
Gilles
Courtois
,
Yosef
Shiloh§,
Michael
Karin
**, and
Galit
Rotman§
From the
Laboratory of Gene Regulation and Signal
Transduction, Department of Pharmacology, University of California
at San Diego, La Jolla, California 92093-0636, § Department of Human Genetics and Molecular Medicine,
Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel, ¶ Department of Medical Physics, Memorial
Sloan-Kettering Cancer Center, New York, New York 10021, and
Unite de Biologie Moleculaire de l'Expression Genique, Institut
Pasteur, 75724 Paris, France
Received for publication, October 26, 2000, and in revised form, December 12, 2000
 |
ABSTRACT |
Following challenge with proinflammatory
stimuli or generation of DNA double strand breaks (DSBs), transcription
factor NF-
B translocates from the cytoplasm to the nucleus to
activate expression of target genes. In addition, NF-
B plays a key
role in protecting cells from proapoptotic stimuli, including DSBs.
Patients suffering from the genetic disorder
ataxia-telangiectasia, caused by mutations in the
ATM gene, are highly sensitive to inducers of DSBs,
such as ionizing radiation. Similar hypersensitivity is displayed by cell lines derived from ataxia-telangiectasia patients or
Atm knockout mice. The ATM protein, a member of the
phosphatidylinositol 3-kinase (PI3K)-like family, is a multifunctional
protein kinase whose activity is stimulated by DSBs. As both ATM and
NF-
B deficiencies result in increased sensitivity to DSBs, we
examined the role of ATM in NF-
B activation. We report that ATM is
essential for NF-
B activation in response to DSBs but not
proinflammatory stimuli, and this activity is mediated via the I
B
kinase complex. DNA-dependent protein kinase, another
member of the PI3K-like family, PI3K itself, and c-Abl, a nuclear
tyrosine kinase, are not required for this response.
 |
INTRODUCTION |
The transcription factor NF-
B is activated by a broad array of
stress-related signals, including proinflammatory cytokines and DNA
damage (1-3). In most cells, NF-
B is sequestered in the cytoplasm
in an inactive form because of tight association with its inhibitors,
the I
Bs. Activation of NF-
B is achieved through signal-induced
phosphorylation of I
B at specific amino-terminal serine residues by
the I
B kinase (IKK)1
complex. This phosphorylation triggers I
B degradation via the ubiquitin-proteasome pathway, resulting in NF-
B translocation into
the nucleus (4). The IKK complex consists of two highly homologous
kinase subunits (IKK
and IKK
) and a nonenzymatic regulatory
component, IKK
/NEMO (5, 6).
NF-
B plays a critical role in cellular protection against a variety
of apoptotic stimuli, including DNA damage (7-11), and inhibition of
NF-
B leads to radiosensitization (12). Acute radiosensitivity is a
hallmark of the human genetic disorder ataxia-telangiectasia (A-T)
(13). This pleiotropic disease is also characterized by progressive
cerebellar degeneration, immunodeficiency, and extreme predisposition
to lymphoreticular malignancies (14). The gene responsible for A-T,
ATM, encodes a multifunctional serine/threonine protein
kinase, which is a member of the phosphatidylinositol 3-kinase
(PI3K)-like family of large proteins (see Refs. 15-17; reviewed in
Ref. 18). Like A-T patients, Atm-null mice are
extremely sensitive to ionizing radiation (IR) (19). Similar
hypersensitivity to a variety of DSB-inducing agents (20, 21),
including the topoisomerase inhibitors etoposide (22) and camptothecin
(CPT) (23), is observed in cultured cells isolated from A-T patients or
Atm-deficient mice.
ATM appears to mediate the response of NF-
B to DSBs, since NF-
B
activation by IR and CPT is reduced or abolished in A-T cells (24, 25).
The DNA-dependent protein kinase (DNA-PK), another member
of the PI3K-like family of protein kinases, has also been implicated in
the activation of NF-
B following exposure to IR (26).
We analyzed the response of the NF-
B pathway to IR and a
radiomimetic agent, neocarzinostatin (NCS), in ATM-deficient murine tissues and human cell lines. Our results clearly indicate that functional ATM is required for the activation of the NF-
B pathway by
agents that induce DSBs but not by proinflammatory stimuli. We also
show that downstream of ATM, the activation of NF-
B requires a
functional IKK complex. Two other protein kinases involved in cellular
responses to DNA damage, c-Abl and DNA-PK, are not required for the
activation of NF-
B by IR. PI3K itself is also not likely to be
involved in this pathway.
 |
EXPERIMENTAL PROCEDURES |
Cell Culture and Cell Extracts--
Human embryonic kidney 293 cells were maintained in Dulbecco's modified Eagle's medium with 10%
fetal bovine serum. Cell extracts were prepared as described previously
(2). Human lymphoblasts were grown in RPMI with 10% fetal bovine serum
and lysed in lysis buffer (10 mM Tris, pH 7.5, 150 mM NaCl, 5 mM EDTA, 1% Nonidet P-40) in the
presence of protease and phosphatase inhibitors.
Mice and Tissue Extracts--
Atm
/
,
DNA-PKcs
/
, Ku70
/
,
and Ku80
/
mice were described previously
(27-30). Adult mice were exposed to 20 Gy of ionizing radiation and
injected with LPS (5 µg/g) or mock-treated. After 75 min mice were
sacrificed, and organs were obtained. Protein extracts were isolated
from liver or kidney in tissue extraction buffer (50 mM
Hepes, pH 7.5, 300 mM NaCl, 1% Triton X-100, 10%
glycerol, 1 mM dithiothreitol) containing protease and
phosphatase inhibitors.
Electrophoretic Mobility Shift Assay (EMSA)--
EMSA was
performed as described previously (2). Briefly, 10 µg of cell extract
or 40 µg of tissue extract were incubated with 2 µg of poly(dI-dC)
and 5,000-10,000 cpm of 32P-labeled oligonucleotide
probes. After 30 min at room temperature, the samples were analyzed on
native 5% polyacrylamide gel. For supershift EMSA, protein extracts
were incubated with 0.5 µg of anti-p65 NF-
B (C-20; Santa Cruz
Biotechnology) or anti-p50 NF-
B (NLS; Santa Cruz
Biotechnology) antibodies for 20 min, after which the labeled
oligonucleotide was added, and incubation was continued for another 20 min. EMSA was also performed in the presence of an excess of unlabeled
B oligonucleotide or AP-1 oligonucleotide to show the specificity of
DNA binding.
Kinase Assay--
Immune-complex IKK assays were performed with
250 µg of mouse tissue extracts that were immunoprecipitated with
anti-IKK
antibody (M-280; Santa Cruz Biotechnology) and protein-A
beads. IKK kinase assays from human cell cultures were carried out with 500 µg of whole cell extracts, using anti-IKK
antibody (B78-1; Pharmingen) and protein A/G-agarose beads. IKK kinase reactions were
carried out as described (2). The presence of equal amounts of IKK
in the kinase reactions was verified by immunoblotting.
Immunoblotting--
For the analysis of I
B
degradation,
cell extracts were electrophoresed on 10% polyacrylamide gels and
blotted onto polyvinylidene difluoride membranes. A rabbit polyclonal
anti-I
B
antibody was used. Tubulin levels were assessed for equal
loading, using a monoclonal antibody (B-5-1-2; Sigma).
 |
RESULTS |
To examine the involvement of PI3K-like kinases in activation of
NF-
B in response to IR, we first tested the effect of the microbial
metabolite wortmannin. At low nanomolar concentrations, wortmannin
inhibits the lipid kinase activity of PI3K. At higher concentrations,
this drug also inhibits PI3K-like protein kinases, including ATM and
DNA-PK (31). Pretreatment of human embryonic kidney 293 cells with
wortmannin at concentrations higher than 20 µM inhibited
IR-induced NF-
B DNA binding, I
B
degradation, and IKK
activation (Fig. 1). It had no effect,
however, on tumor necrosis factor (TNF)-induced NF-
B or IKK
activation. Similar results were obtained with HeLa cells (data not
shown). It should be noted that at 2 µM, a concentration
fully sufficient for inhibition of PI3K activity, wortmannin had no
effect on the activation of NF-
B by IR. Thus, one or more members of
the PI3K-like protein family, but not PI3K itself, are involved in
IR-induced NF-
B activation.

View larger version (39K):
[in this window]
[in a new window]
|
Fig. 1.
Wortmannin inhibits IR-induced
NF- B activation,
I B degradation, and
IKK activation. Human embryonic kidney 293 cells were pretreated
for 1 h with various concentrations of wortmannin before exposure
to IR or TNF. Cell extracts were prepared 1 h after exposure to IR
(20 Gy) or 15 min after treatment with TNF (10 ng/ml). Un,
untreated. A, NF- B DNA binding activity was measured by
EMSA (upper panel). NF-1 DNA binding activity was determined
as a loading control (lower panel). B, I B
degradation was assessed by immunoblotting with anti-I B
antibodies. C, IKK kinase activity was measured by
immune-complex kinase assay using glutathione
S-transferase-I B (GST-I B )
as a substrate (upper panel). IKK protein levels were
determined by immunoblotting with anti-IKK antibody, as a loading
control (lower panel).
|
|
We further investigated the involvement of ATM in the NF-
B response
to IR using wild type (wt) and Atm
/
mice.
Intraperitoneal injection of LPS activated NF-
B DNA binding activity in the liver of both wt and Atm
/
mice. Exposure to IR, however, induced NF-
B DNA binding activity in
wt but not in Atm
/
mice (Fig.
2A). Kidney extracts yielded
similar results (Fig. 2B). IR-elicited NF-
B binding
activity contained p65 and p50 NF-
B proteins in the liver and p50 in
the kidney, as revealed by antibody supershift experiments. These
results indicate that in vivo, ATM is required for the
activation of NF-
B in response to IR but not for induction of this
pathway by LPS. To determine whether ATM is also required for
IR-induced IKK activation, IKK kinase activity was analyzed in liver
protein extracts derived from wt and Atm
/
mice. LPS treatment resulted in activation of IKK in both types of
mice, whereas IR lead to activation of IKK in wt but not
Atm
/
mice (Fig. 2C). These
observations clearly demonstrate that in vivo, ATM is
required for IR-induced activation of the entire IKK-NF-
B
pathway.

View larger version (42K):
[in this window]
[in a new window]
|
Fig. 2.
ATM is required for IR-induced
NF- B and IKK activation. Wild type (+/+)
and Atm-null ( / ) mice were left untreated (Un), exposed
to 20 Gy of IR, or injected with LPS (5 µg/g). Protein extracts were
isolated 75 min later from liver (A) or kidney
(B) and used in EMSA to measure NF- B DNA binding
activity. Equal loading is demonstrated by NF-1 binding activity. EMSA
was also performed after incubation of protein extracts with anti-p65
or anti-p50 antibodies to examine the protein composition of NF- B,
or in the presence of an excess of unlabeled AP-1 or B oligo to
demonstrate the specificity of DNA binding. Because NF-1 activity was
not detectable in kidney extracts, equal loading was examined by
immunoblotting with anti-c-Jun NH2-terminal kinase 1 antibody (JNK1). C, the liver protein extracts
described in A were immunoprecipitated with anti-IKK and
subjected to immune-complex kinase assay using glutathione
S-transferase-I B GST-I B ;
(1-54) as substrate (upper panel) or immunoblotting with
anti-IKK antibody (lower panel).
|
|
Similar studies were carried out in mice deficient for each of the
three components of the DNA-PK holoenzyme: the catalytic subunit
(DNA-PKcs), and the DNA-binding regulatory subunit, the Ku heterodimer
(Ku70/Ku80). Unlike Atm
/
mice, the induction
of NF-
B DNA binding activity in response to either IR or LPS
treatment was intact in livers and kidneys of
DNA-PKcs
/
, Ku70
/
,
and Ku80
/
mice (Fig.
3). Normal NF-
B induction in response
to IR was also detected in c-Abl-null mice (Fig.
4). These results indicate that DNA-PK
and c-Abl are not required for the IR-induced activation of the NF-
B
pathway in vivo.

View larger version (64K):
[in this window]
[in a new window]
|
Fig. 3.
DNA-PK is not required for IR-induced
NF- B activation. Wild type (+/+),
DNA-PKcs / (PK / ),
Ku70 / , and Ku80 /
mice were treated with IR or LPS as described for Fig. 2. Protein
extracts were isolated from liver (A) or kidney
(B) and used in EMSA to measure NF- B DNA binding
activity. Un, untreated; JNK1, c-Jun
NH2-terminal kinase 1.
|
|

View larger version (72K):
[in this window]
[in a new window]
|
Fig. 4.
c-Abl is not required for IR-induced
NF- B activation. Wild type (+/+) and
c-Abl / ( / ) mice were exposed
to IR as described for Fig. 2. Protein extracts were isolated from
liver or kidney and used in EMSA to measure NF- B DNA binding
activity (upper panel). Equal protein loading was examined
by immunoblotting with anti-c-Jun NH2-terminal kinase 1 antibody (lower panel).
|
|
The role of ATM in IKK activation and I
B
degradation was also
studied in human lymphoblasts. The responses to IR and to the
radiomimetic drug NCS were defective in A-T lymphoblasts (Fig. 5, A and B),
whereas the response to phorbol 12-myristate 13-acetate (PMA) was
intact in these cells (Fig. 5C). These results further support the above observations, indicating that a functional ATM is
required for the induction of IKK by DSBs. It is noteworthy that the
DSB-induced activation of IKK in A-T lymphoblasts appears reduced and
delayed but not completely abolished. This pattern is reminiscent of
other signaling pathways mediated by ATM and reflects the involvement
of other kinases, possibly ATR, in the late response to DSBs (reviewed
in Ref. 18).

View larger version (20K):
[in this window]
[in a new window]
|
Fig. 5.
ATM is required for IR- and NCS-induced
I B degradation and
IKK activation in human lymphoblasts. Protein extracts were
obtained from A-T and control lymphoblasts at different time points
after exposure to 20 Gy of IR (A), 250 ng/ml NCS
(B), or 10 ng/ml PMA (C). Degradation of I B
was assessed by immunoblotting (top panels). Tubulin served
as a loading control. IKK kinase activity was measured by
immune-complex kinase assay using glutathione
S-transferase-I B (GST-I B )
as a substrate (bottom panels).
|
|
The regulatory subunit of the IKK complex, IKK
/NEMO, is required for
the activation of the IKK-NF-
B pathway by a large variety of
proinflammatory stimuli (see Ref. 32; reviewed in Refs. 5 and 6). This
requirement has not been demonstrated, however, in response to DNA
damage. We analyzed the involvement of IKK
/NEMO in the response to
DSBs, using a murine preB cell line, 70Z/3, and its
IKK
/NEMO-deficient derivative, 1.3E2 (32). The degradation of
I
B
and activation of IKK were completely abolished in the IKK
/NEMO-deficient cells in response to either NCS (Fig.
6A) or PMA (Fig.
6B). These results indicate that IKK
/NEMO is essential for activation of this pathway also in response to DSBs.

View larger version (47K):
[in this window]
[in a new window]
|
Fig. 6.
IKK /NEMO is required
for NCS- and PMA-induced I B
degradation and IKK activation in murine cells. Protein
extracts were obtained from wt murine preB cells (70Z/3) and
its IKK/NEMO/ -deficient derivative (1.3E2) at
different time points after exposure to 250 ng/ml NCS (A) or
100 ng/ml PMA (B). Protein levels of I B (top
panels) and IKK kinase activity (bottom panels) were
measured as described in Fig. 5. GST-I B ,
glutathione S-transferase-I B .
|
|
 |
DISCUSSION |
Our results clearly demonstrate that ATM is essential for
activation of the entire NF-
B pathway by DSBs in both cultured human
cells and mouse tissues, including IKK activation, I
B
degradation, and induction of NF-
B DNA binding activity. ATM is not
required for activation of this pathway by proinflammatory stimuli,
such as TNF, PMA, or LPS.
The activity of c-Abl, a nuclear tyrosine kinase, is stimulated by IR
in an ATM-dependent manner (33, 34). In addition, ATM
interacts with c-Abl and phosphorylates it in vitro (33, 34). A functional interaction has also been suggested between c-Abl and
DNA-PK in the response to DNA damage (35, 36). Our results indicate
that neither c-Abl nor DNA-PK are required for IR-induced NF-
B
activation, because mice lacking c-Abl, or each of the subunits of the
DNA-PK holoenzyme, display a normal NF-
B response to IR.
Our data are in agreement with previous observations showing that
CPT-induced NF-
B activation depends on ATM but not on DNA-PK (25).
However, another study implicated DNA-PK in the activation of NF-
B
by IR (26). The apparent discrepancy between these observations might
be due to differences in the degree or type of damage caused by IR
versus CPT. In addition, the DNA-PK-deficient MO59J cell
line used in those experiments has very low levels of ATM expression
(37), and although it is deficient in DNA-PK, it probably exhibits
suboptimal activation of ATM-dependent effector functions.
ATM was suggested to directly phosphorylate I
B
itself in
vitro on its carboxyl terminus (38). However, the physiological significance of this observation is not clear. In vitro
phosphorylation by DNA-PK on residues in the carboxyl terminus of
I
B
enhanced its ability to associate with NF-
B and to inhibit
NF-
B DNA binding properties (39), suggesting a role for DNA-PK in
down-regulation of NF-
B and termination of the NF-
B response.
Direct phosphorylation of I
B
by ATM, if occurring in
vivo, might play a similar role.
The vast majority of the signals that induce activation of the latent
NF-
B complex originate at ligand-receptor interactions on the cell
membrane and require IKK activation. However, the activation of NF-
B
by two types of DNA-damaging agents, short wavelength UV and IR, was
found to proceed through distinct mechanisms (2). NF-
B activation in
response to UV radiation is neither mediated through damage to nuclear
DNA (40), nor does it depend on IKK activation or amino-terminal
I
B
phosphorylation, although it still involves
proteasome-mediated I
B
degradation (2, 41). Unlike UV radiation,
exposure to IR leads to activation of IKK and subsequent induction of
phosphorylation-dependent I
B
degradation (2). A
recent study shows that activation of NF-
B in response to DSBs, such
as those generated by the DNA topoisomerase I inhibitor CPT, depends on
initial nuclear damage followed by cytoplasmic signaling events (42).
This could explain the marked difference in the kinetics and intensity
of IKK and NF-
B activation by DNA-damaging agents versus
proinflammatory stimuli (see Refs. 2 and 24 and Fig. 5).
The mechanism by which DSBs activate NF-
B is still not entirely
clear. The data presented here point to a critical role for ATM in
DSB-induced NF-
B activation. The involvement of the IKK complex in
this response is further supported by our observation that mutant cells
lacking IKK
/NEMO are unable to activate this pathway in
response to NCS. ATM is primarily a nuclear protein that plays a
crucial role in the rapid and efficient induction of multiple signaling
pathways in response to DSBs, leading to repair of DNA damage and
activation of cell cycle checkpoints and cellular stress responses
(18). Its involvement in the response of NF-
B to DSBs suggests that
the initial nuclear signaling events in this pathway are triggered by
ATM. It is unclear at this point how this signal then translocates to
the cytoplasm to activate the IKK complex.
Impaired activation of NF-
B leads to enhanced apoptosis in response
to IR (10, 12, 43) and other agents that induce DSBs, such as CPT (42).
It is still not clear how the absence of ATM leads to the
hypersensitivity to DSBs exhibited by A-T cells. It appears that
defective activation of cell cycle checkpoints does not necessarily
contribute to this aspect of the A-T phenotype. It has been suggested
that a subtle defect in DSB repair may underlie this increased
sensitivity (44). However, it is also conceivable that a defect in the
induction of anti-apoptotic genes responsive to NF-
B contributes to
enhanced cell death of A-T cells in response to DSBs.
 |
ACKNOWLEDGEMENTS |
We thank Drs. Alain Israel and Yinon Ben
Neriah for reagents and helpful discussions.
 |
FOOTNOTES |
*
This work was supported in part by research grants from the
Department of Energy (DE-FG03-8GER60429) and the National Institutes of
Health (Ca76188) (to M. K.), by the A-T Medical Research Foundation and A-T Children's Project, and by the Thomas Appeal (to Y. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
**
To whom correspondence should be addressed: Laboratory of Gene
Regulation and Signal Transduction, Dept. of Pharmacology, University of California at San Diego, 9500 Gillman Dr., La Jolla, CA 92093-0636. Tel.: 858-534-8158; Fax: 858-534-1361; E-mail: karin-office@ucsd.edu.
Published, JBC Papers in Press, December 12, 2000, DOI 10.1074/jbc.M009809200
 |
ABBREVIATIONS |
The abbreviations used are:
IKK, I
B kinase;
A-T, ataxia-telangiectasia;
PI3K, phosphatidylinositol 3-kinase;
IR, ionizing radiation;
DSB(s), double strand break(s);
CPT, camptothecin;
DNA-PK, DNA-dependent protein kinase;
NCS, neocarzinostatin;
Gy, gray;
LPS, lipopolysaccharide;
TNF, tumor
necrosis factor;
wt, wild type;
PMA, phorbol 12-myristate
13-acetate.
 |
REFERENCES |
1.
|
Baldwin, A. S.
(1996)
Annu. Rev. Immunol.
14,
649-681[CrossRef][Medline]
[Order article via Infotrieve]
|
2.
|
Li, N.,
and Karin, M.
(1998)
Proc. Natl. Acad. Sci. U. S. A.
95,
13012-13017[Abstract/Free Full Text]
|
3.
|
Mercurio, F.,
and Manning, A. M.
(1999)
Oncogene
18,
6163-6171[CrossRef][Medline]
[Order article via Infotrieve]
|
4.
|
Karin, M.,
and Ben Neriah, Y.
(2000)
Annu. Rev. of Immunol.
18,
621-663[CrossRef][Medline]
[Order article via Infotrieve]
|
5.
|
Karin, M.
(1999)
Oncogene
18,
6867-6874[CrossRef][Medline]
[Order article via Infotrieve]
|
6.
|
Israel, A.
(2000)
Trends Cell Biol.
10,
129-133[CrossRef][Medline]
[Order article via Infotrieve]
|
7.
|
Beg, A. A.,
and Baltimore, D.
(1996)
Science
274,
782-784[Abstract/Free Full Text]
|
8.
|
Liu, Z. G.,
Hsu, H.,
Goeddel, D. V.,
and Karin, M.
(1996)
Cell
87,
565-576[Medline]
[Order article via Infotrieve]
|
9.
|
Van Antwerp, D. J.,
Martin, S. J.,
Kafri, T.,
Green, D. R.,
and Verma, I. M.
(1996)
Science
274,
787-789[Abstract/Free Full Text]
|
10.
|
Wang, C.-Y.,
Mayo, M. W.,
and Baldwin, A. S., Jr.
(1996)
Science
274,
784-787[Abstract/Free Full Text]
|
11.
|
Wang, C.-Y.,
Mayo, M. W.,
Korneluk, R. G.,
Goeddel, D. V.,
and Baldwin, A. S., Jr.
(1998)
Science
281,
1680-1683[Abstract/Free Full Text]
|
12.
|
Yamagishi, N.,
Miyakoshi, J.,
and Takebe, H.
(1997)
Int. J. Radiat. Biol.
72,
157-162[CrossRef][Medline]
[Order article via Infotrieve]
|
13.
|
Lavin, M. F.
(1998)
Radiother. Oncol.
47,
113-123[CrossRef][Medline]
[Order article via Infotrieve]
|
14.
|
Lavin, M. F.,
and Shiloh, Y.
(1997)
Annu. Rev. Immunol.
15,
177-202[CrossRef][Medline]
[Order article via Infotrieve]
|
15.
|
Savitsky, K.,
Bar-Shira, A.,
Gilad, S.,
Rotman, G.,
Ziv, Y.,
Vanagaite, L.,
Tagle, D. A.,
Smith, S.,
Uziel, T.,
Sfez, S.,
Ashkenazi, M.,
Pecker, I.,
Frydman, M.,
Harnik, R.,
Patanjali, S. R.,
Simmons, A.,
Clines, G. A.,
Sartiel, A.,
Gatti, R. A.,
Chessa, L.,
Sanal, O.,
Lavin, M. F.,
Jaspers, N. G. J.,
Taylor, A. M. R.,
Arlett, C. F.,
Miki, T.,
Weissman, S.,
Lovett, M.,
Collins, F. S.,
and Shiloh, Y.
(1995)
Science
268,
1749-1753[Medline]
[Order article via Infotrieve]
|
16.
|
Banin, S.,
Moyal, L.,
Shieh, S.-Y.,
Taya, Y.,
Anderson, C. W.,
Chessa, L.,
Smorodinsky, N. I.,
Prives, C.,
Reiss, Y.,
Shiloh, Y.,
and Ziv, Y.
(1998)
Science
281,
1674-1677[Abstract/Free Full Text]
|
17.
|
Canman, C. E.,
Lim, D.-S.,
Cimprich, K. A.,
Taya, Y.,
Tamai, K.,
Sakaguchi, K.,
Appella, E.,
Kastan, M. B.,
and Siliciano, J. D.
(1998)
Science
281,
1677-1679[Abstract/Free Full Text]
|
18.
|
Rotman, G.,
and Shiloh, Y.
(1999)
Oncogene
18,
6135-6144[CrossRef][Medline]
[Order article via Infotrieve]
|
19.
|
Barlow, C.,
Hirotsune, S.,
Paylor, R.,
Liyanage, M.,
Eckhaus, M.,
Collins, F.,
Shiloh, Y.,
Crawley, J. N.,
Ried, T.,
Tagle, D.,
and Wynshaw-Boris, A.
(1996)
Cell
86,
159-171[Medline]
[Order article via Infotrieve]
|
20.
|
McKinnon, P. J.
(1987)
Hum. Genet.
75,
197-208[Medline]
[Order article via Infotrieve]
|
21.
|
Westphal, C. H.,
Hoyes, K. P.,
Canman, C. E.,
Huang, X.,
Kastan, M. B.,
Hendry, J. H.,
and Leder, P.
(1998)
Cancer Res.
58,
5637-5639[Abstract]
|
22.
|
Caporossi, D.,
Porfirio, B.,
Nicoletti, B.,
Palitti, F.,
Degrassi, F.,
De Salvia, R.,
and Tanzarella, C.
(1993)
Mut. Res.
290,
265-272[Medline]
[Order article via Infotrieve]
|
23.
|
Johnson, R. T.,
Gotoh, E.,
Mullinger, A. M.,
Ryan, A. J.,
Shiloh, Y.,
Ziv, Y.,
and Squires, S.
(1999)
Biochem. Biophys. Res. Commun.
261,
317-325[CrossRef][Medline]
[Order article via Infotrieve]
|
24.
|
Lee, S.-J.,
Dimtchev, A.,
Lavin, M. F.,
Dritschilo, A.,
and Jung, M.
(1998)
Oncogene
17,
1821-1826[CrossRef][Medline]
[Order article via Infotrieve]
|
25.
|
Piret, B.,
Schoonbroodt, S.,
and Piette, J.
(1999)
Oncogene
18,
2261-2271[CrossRef][Medline]
[Order article via Infotrieve]
|
26.
|
Basu, S.,
Rosenzweig, K. R.,
Youmell, M.,
and Price, B. D.
(1998)
Biochem. Biophys. Res. Comm.
247,
79-83[CrossRef][Medline]
[Order article via Infotrieve]
|
27.
|
Xu, Y.,
Ashley, T.,
Brainerd, E. E.,
Bronson, R. T.,
Meyn, S. M.,
and Baltimore, D.
(1996)
Genes Dev.
10,
2411-2422[Abstract]
|
28.
|
Nussenzweig, A.,
Chen, C.,
da Costa,
Soares, V.,
Sanchez, M.,
Sokol, K.,
Nussenzweig, M. C.,
and Li, G. C.
(1996)
Nature
382,
551-555[CrossRef][Medline]
[Order article via Infotrieve]
|
29.
|
Li, G. C.,
Ouyang, H.,
Li, X.,
Nagasawa, H.,
Little, J. B.,
Chen, D. J.,
Ling, C. C.,
Fuks, Z.,
and Cordon-Cardo, C.
(1998)
Mol. Cell
2,
1-8[Medline]
[Order article via Infotrieve]
|
30.
|
Kurimasa, A.,
Ouyang, H.,
Dong, L. J.,
Wang, S.,
Li, X.,
Cordon-Cardo, C.,
Chen, D. J.,
and Li, G. C.
(1999)
Proc. Natl. Acad. Sci. U. S. A.
96,
1403-1408[Abstract/Free Full Text]
|
31.
|
Sarkaria, J. N.,
Tibbetts, R. S.,
Busby, E. C.,
Kennedy, A. P.,
Hill, D. E.,
and Abraham, R. T.
(1998)
Cancer Res.
58,
4375-4382[Abstract]
|
32.
|
Yamaoka, S.,
Courtois, G.,
Bessia, C.,
Whiteside, S. T.,
Weil, R.,
Agou, F.,
Kirk, H. E.,
Kay, R. J.,
and Israel, A.
(1998)
Cell
93,
1231-1240[Medline]
[Order article via Infotrieve]
|
33.
|
Baskaran, R.,
Wood, L. D.,
Whitaker, L. L.,
Canman, C. E.,
Morgan, S. E.,
Xu, Y.,
Barlow, C.,
Baltimore, D.,
Wynshaw-Boris, A.,
Kastan, M. B.,
and Wang, J. Y. J.
(1997)
Nature
387,
516-519[CrossRef][Medline]
[Order article via Infotrieve]
|
34.
|
Shafman, T.,
Khanna, K. K.,
Kedar, P.,
Spring, K.,
Kozlov, S.,
Yen, T.,
Hobson, K.,
Gatei, M.,
Zhang, N.,
Watters, D.,
Egerton, M.,
Shiloh, Y.,
Kharbanda, S.,
Kufe, D.,
and Lavin, M. F.
(1997)
Nature
387,
520-523[CrossRef][Medline]
[Order article via Infotrieve]
|
35.
|
Kharbanda, S.,
Pandey, P.,
Jin, S.,
Inoue, S.,
Bharti, A.,
Yuan, Z.-M.,
Weichselbaum, R.,
Weaver, D.,
and Kufe, D.
(1997)
Nature
386,
732-735[CrossRef][Medline]
[Order article via Infotrieve]
|
36.
|
Jin, S.,
Kharbanda, S.,
Mayer, B.,
Kufe, D.,
and Weaver, D. T.
(1997)
J. Biol. Chem.
272,
24763-24766[Abstract/Free Full Text]
|
37.
|
Chan, D. W.,
Gately, D. P.,
Urban, S.,
Galloway, A. M.,
Lees-Miller, S. P.,
Yen, T.,
and Allalunis-Turner, J.
(1998)
Int. J. Radiat. Biol.
74,
217-224[CrossRef][Medline]
[Order article via Infotrieve]
|
38.
|
Jung, M.,
Kondratyev, A.,
Lee, S. A.,
Dimtchev, A.,
and Dritschilo, A.
(1997)
Cancer Res.
57,
24-27[Abstract]
|
39.
|
Liu, L.,
Kwak, Y. T.,
Bex, F.,
Garcia-Martinez, L. F.,
Li, X. H.,
Meek, K.,
Lane, W. S.,
and Gaynor, R. B.
(1998)
Mol. Cell. Biol.
18,
4221-4234[Abstract/Free Full Text]
|
40.
|
Devary, Y.,
Rosette, C.,
DiDonato, J. A.,
and Karin, M.
(1993)
Science
261,
1442-1445[Medline]
[Order article via Infotrieve]
|
41.
|
Bender, K.,
Gottlicher, M.,
Whiteside, S.,
Rahmsdorf, H. J.,
and Herrlich, P.
(1998)
EMBO J.
17,
5170-5181[Abstract/Free Full Text]
|
42.
|
Huang, T. T.,
Wuerzberger-Davis, S. M.,
Seufzer, B. J.,
Shumway, S. D.,
Kurama, T.,
Boothman, D. A.,
and Miyamoto, S.
(2000)
J. Biol. Chem.
275,
9501-9509[Abstract/Free Full Text]
|
43.
|
Jung, M.,
Zhang, Y.,
Dimtchev, A.,
and Dritschilo, A.
(1998)
Radiat. Res.
149,
596-601[Medline]
[Order article via Infotrieve]
|
44.
|
Jeggo, P. A.,
Carr, A. M.,
and Lehmann, A. R
(1998)
Trends Genet.
14,
312-316[CrossRef][Medline]
[Order article via Infotrieve]
|
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.