ATM and the catalytic subunit of DNA-dependent protein kinase activate NF-kappaB through a common MEK/extracellular signal-regulated kinase/p90(rsk) signaling pathway in response to distinct forms of DNA damage - PubMed (original) (raw)

ATM and the catalytic subunit of DNA-dependent protein kinase activate NF-kappaB through a common MEK/extracellular signal-regulated kinase/p90(rsk) signaling pathway in response to distinct forms of DNA damage

Ganesh R Panta et al. Mol Cell Biol. 2004 Mar.

Abstract

We have identified a novel pathway of ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) signaling that results in nuclear factor kappaB (NF-kappaB) activation and chemoresistance in response to DNA damage. We show that the anthracycline doxorubicin (DOX) and its congener N-benzyladriamycin (AD 288) selectively activate ATM and DNA-PK, respectively. Both ATM and DNA-PK promote sequential activation of the mitogen-activated protein kinase (MAPK)/p90(rsk) signaling cascade in a p53-independent fashion. In turn, p90(rsk) interacts with the IkappaB kinase 2 (IKK-2) catalytic subunit of IKK, thereby inducing NF-kappaB activity and cell survival. Collectively, our findings suggest that distinct members of the phosphatidylinositol kinase family activate a common prosurvival MAPK/IKK/NF-kappaB pathway that opposes the apoptotic response following DNA damage.

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Figures

FIG. 1.

FIG. 1.

The IKK complex mediates NF-κB activation and cell survival in response to anthracycline treatment. (A) P53 null (10)1 murine embryo fibroblasts were treated for the indicated times with 5 μM DOX or 5 μM AD 288. To measure the levels of NF-κB binding activity, nuclear extracts (5 μg) were subjected to EMSA using the upstream NF-κB element from the c-myc gene (URE-κB) as a probe (11). Band 1, classical NF-κB (p65/p50); band 2, p50 homodimers. As control for equal loading, EMSA was also performed with an Octamer-1 (Oct-1) probe. (B) (10)1 cells were treated for 10 min with 2 μg of CHX/ml, followed by incubation for 3 h in the presence or absence of DOX (5 μM). Nuclear extracts (5 μg) were subjected to EMSA as described above. Bands were quantified by densitometric analysis and are expressed as the ratios of the optical density (O.D.) of NF-κB to that of Oct-1. (C) (10)1 cells were treated for the indicated times with 5 μM DOX, and WCEs were isolated in kinase buffer. WCEs were immunoprecipitated (IP) with antibodies against IKK-1 and -2, and an aliquot was subjected to a kinase assay using IκB-α-GST as the substrate (top). An equal aliquot of each immunoprecipitant was subjected to immunoblotting (IB) as indicated (bottom). (D) (10)1 cells were infected with 10 PFU of adenovirus constructs directing expression of wild-type (wt) IKK-2 or IKK-2 K>M for 24 h. Subsequently, cells were treated for 5 h with 5 μM DOX, 5 μM AD 288, or DMSO carrier solution. Alternatively, cells were treated for 30 min with 20 ng of TNF-α/ml or bovine serum albumin carrier solution. Nuclear extracts (5 μg) were subjected to EMSA using as a probe the URE-κβ or the Oct-1 oligonucleotide. (E) HEK 293 cells were plated in triplicate in 96-well plates and transfected by lipofection with 50 ng of NF-κB-luciferase construct in the presence of the indicated amount of wtIKKAP or IKKAPΔC expression vectors and, as an internal control, a Renilla luciferase expression plasmid. Total DNA concentration was adjusted to 150 ng with backbone vector (pcDNA). Following 24 h of treatment with 5 μM DOX, luciferase activity was measured and expressed as induction relative to that of DMSO-treated cells, which was set at 1. Means and standard deviations are representative of three independent experiments carried out in triplicate. (F) Cultures of wild-type and RelA null NIH 3T3 cells were incubated in medium containing 5 μM DOX, 5 μM AD 288, or DMSO carrier solution for 24 and 48 h. Cell proliferation was monitored by conversion of MTS to its formazan product. Means and standard deviations are representative of three independent experiments carried out in triplicate.

FIG. 1.

FIG. 1.

The IKK complex mediates NF-κB activation and cell survival in response to anthracycline treatment. (A) P53 null (10)1 murine embryo fibroblasts were treated for the indicated times with 5 μM DOX or 5 μM AD 288. To measure the levels of NF-κB binding activity, nuclear extracts (5 μg) were subjected to EMSA using the upstream NF-κB element from the c-myc gene (URE-κB) as a probe (11). Band 1, classical NF-κB (p65/p50); band 2, p50 homodimers. As control for equal loading, EMSA was also performed with an Octamer-1 (Oct-1) probe. (B) (10)1 cells were treated for 10 min with 2 μg of CHX/ml, followed by incubation for 3 h in the presence or absence of DOX (5 μM). Nuclear extracts (5 μg) were subjected to EMSA as described above. Bands were quantified by densitometric analysis and are expressed as the ratios of the optical density (O.D.) of NF-κB to that of Oct-1. (C) (10)1 cells were treated for the indicated times with 5 μM DOX, and WCEs were isolated in kinase buffer. WCEs were immunoprecipitated (IP) with antibodies against IKK-1 and -2, and an aliquot was subjected to a kinase assay using IκB-α-GST as the substrate (top). An equal aliquot of each immunoprecipitant was subjected to immunoblotting (IB) as indicated (bottom). (D) (10)1 cells were infected with 10 PFU of adenovirus constructs directing expression of wild-type (wt) IKK-2 or IKK-2 K>M for 24 h. Subsequently, cells were treated for 5 h with 5 μM DOX, 5 μM AD 288, or DMSO carrier solution. Alternatively, cells were treated for 30 min with 20 ng of TNF-α/ml or bovine serum albumin carrier solution. Nuclear extracts (5 μg) were subjected to EMSA using as a probe the URE-κβ or the Oct-1 oligonucleotide. (E) HEK 293 cells were plated in triplicate in 96-well plates and transfected by lipofection with 50 ng of NF-κB-luciferase construct in the presence of the indicated amount of wtIKKAP or IKKAPΔC expression vectors and, as an internal control, a Renilla luciferase expression plasmid. Total DNA concentration was adjusted to 150 ng with backbone vector (pcDNA). Following 24 h of treatment with 5 μM DOX, luciferase activity was measured and expressed as induction relative to that of DMSO-treated cells, which was set at 1. Means and standard deviations are representative of three independent experiments carried out in triplicate. (F) Cultures of wild-type and RelA null NIH 3T3 cells were incubated in medium containing 5 μM DOX, 5 μM AD 288, or DMSO carrier solution for 24 and 48 h. Cell proliferation was monitored by conversion of MTS to its formazan product. Means and standard deviations are representative of three independent experiments carried out in triplicate.

FIG. 2.

FIG. 2.

The MEK/ERK signaling pathway mediates NF-κB activation by DOX and AD 288. (A and B) Serum-starved (10)1 cells were treated for the indicated times with 5 μM DOX or 5 μM AD 288. WCEs (40 μg) were subjected to immunoblotting (IB) using a phospho-specific ERK antibody (pERK1,2), an antibody against phospho-MEK (S218/S222; pMEK1,2), or antibodies that recognize total ERKs (totERK1,2) or total MEKs (totMEK1,2). For equal loading, the same filters were hybridized with an antibody against actin. (C) (10)1 cells were treated for 5 h with 5 μM DOX or 5 μM AD 288 with or without PD98059 (50 μM) or UO126 (20 μM). Nuclear extracts (5 μg) were subjected to EMSA using the URE-κB or Oct-1 probes. O.D., optical density. (D) (10)1 val cells were treated at the nonpermissive temperature of 39°C for the indicated times with 5 μM DOX in the presence or absence of PD98059 (100 μM). Nuclear extracts (5 μg) were subjected to EMSA as described above. (E) (10)1 val cells were treated at the nonpermissive temperature of 39°C for 1 h with 20 ng of TNF-α/ml with or without PD98059 (PD; 50 to 100 μM) or UO126 (UO; 10 to 20 μM). Nuclear extracts (5 μg) were subjected to EMSA as described above. (F) (10)1 cells were treated for 2 h with 5 μM DOX or 5 μM AD 288 with or without PD98059 (100 μM). The IκB kinase assay was performed as described in the legend of Fig. 1. (G) HEK 293 cells were plated in triplicate in 96-well plates and transfected by lipofection with 50 ng of the NF-κB-luciferase construct in the presence of the indicated amount of dominant negative (dn) MEK expression vector and, as an internal control, a Renilla luciferase expression plasmid. The final DNA concentration was adjusted to 150 ng with the parental control vector pCMV. Following 24 h of treatment with 5 μM DOX, luciferase activity was determined as described in the legend of Fig. 1. Means and standard deviations (bars) are representative of three independent experiments carried out in triplicate. (H) HEK 293 cells were lipofected with 100 nM siRNA specific for ERK2 (si-ERK2) or 100 nM nonspecific siRNA control (si-cont). After 48 h of transfection, cells were treated for 2 h with 5 μM DOX or DMSO carrier solution and WCEs were subjected to immunoblotting with an antibody specific for ERK-1 and -2 (top) or an antibody that recognizes IKK-1 and -2 phosphorylated at serines 180 and 181, respectively (middle). The same blot was also hybridized with an antibody against actin (bottom). (I) (10)1 val cells were treated for 1 h in the presence or absence of PD98059 (50 μM). Cells were then irradiated with 80 Gy and incubated at 39°C for 3 h. Nuclear extracts (5 μg) were subjected to EMSA as described above.

FIG. 2.

FIG. 2.

The MEK/ERK signaling pathway mediates NF-κB activation by DOX and AD 288. (A and B) Serum-starved (10)1 cells were treated for the indicated times with 5 μM DOX or 5 μM AD 288. WCEs (40 μg) were subjected to immunoblotting (IB) using a phospho-specific ERK antibody (pERK1,2), an antibody against phospho-MEK (S218/S222; pMEK1,2), or antibodies that recognize total ERKs (totERK1,2) or total MEKs (totMEK1,2). For equal loading, the same filters were hybridized with an antibody against actin. (C) (10)1 cells were treated for 5 h with 5 μM DOX or 5 μM AD 288 with or without PD98059 (50 μM) or UO126 (20 μM). Nuclear extracts (5 μg) were subjected to EMSA using the URE-κB or Oct-1 probes. O.D., optical density. (D) (10)1 val cells were treated at the nonpermissive temperature of 39°C for the indicated times with 5 μM DOX in the presence or absence of PD98059 (100 μM). Nuclear extracts (5 μg) were subjected to EMSA as described above. (E) (10)1 val cells were treated at the nonpermissive temperature of 39°C for 1 h with 20 ng of TNF-α/ml with or without PD98059 (PD; 50 to 100 μM) or UO126 (UO; 10 to 20 μM). Nuclear extracts (5 μg) were subjected to EMSA as described above. (F) (10)1 cells were treated for 2 h with 5 μM DOX or 5 μM AD 288 with or without PD98059 (100 μM). The IκB kinase assay was performed as described in the legend of Fig. 1. (G) HEK 293 cells were plated in triplicate in 96-well plates and transfected by lipofection with 50 ng of the NF-κB-luciferase construct in the presence of the indicated amount of dominant negative (dn) MEK expression vector and, as an internal control, a Renilla luciferase expression plasmid. The final DNA concentration was adjusted to 150 ng with the parental control vector pCMV. Following 24 h of treatment with 5 μM DOX, luciferase activity was determined as described in the legend of Fig. 1. Means and standard deviations (bars) are representative of three independent experiments carried out in triplicate. (H) HEK 293 cells were lipofected with 100 nM siRNA specific for ERK2 (si-ERK2) or 100 nM nonspecific siRNA control (si-cont). After 48 h of transfection, cells were treated for 2 h with 5 μM DOX or DMSO carrier solution and WCEs were subjected to immunoblotting with an antibody specific for ERK-1 and -2 (top) or an antibody that recognizes IKK-1 and -2 phosphorylated at serines 180 and 181, respectively (middle). The same blot was also hybridized with an antibody against actin (bottom). (I) (10)1 val cells were treated for 1 h in the presence or absence of PD98059 (50 μM). Cells were then irradiated with 80 Gy and incubated at 39°C for 3 h. Nuclear extracts (5 μg) were subjected to EMSA as described above.

FIG. 3.

FIG. 3.

p90_rsk_ mediates IKK complex and NF-κB activation by anthracyclines through association with the IKK-2 subunit. (A) (10)1 cells were treated at the indicated time points with 5 μM DOX or 5 μM AD 288 in the absence or presence of PD98059 (100 μM). Following immunoprecipitation (IP) with an antibody against p90_rsk_, a kinase assay using IκB-α-GST as the substrate was performed (top). An equal aliquot of each immunoprecipitant was subjected to immunoblotting (IB) as indicated (bottom) with an anti-p90_rsk_ antibody. ns, nonspecific. (B) HEK 293 cells were plated in triplicate in 96-well plates and transfected by lipofection with 50 ng of NF-κB-luciferase construct in the presence of the indicated amount of empty vector (pcDNA) or vectors directing expression of either the wild-type (wt) or dominant negative (D205N) p90_rsk_ gene. Following 24 h of treatment with 5 μM DOX, luciferase activity was determined as described in the legend of Fig. 1. Means and standard deviations are representative of three independent experiments carried out in triplicate. Bars represent standard deviations. (C) HEK 293 cells were transfected by lipofection with vectors directing expression of N-terminally HA-tagged p90_rsk_ (HA-p90_rsk_) or Flag-tagged IKK-2 (Flag-IKK-2). Transfected cells were treated for 2 h with 5 μM DOX or DMSO carrier solution. Following immunoprecipitation with an antibody (Ab) against Flag (i) or against HA (ii), immunoblotting with equal immunoprecipitated aliquots of either IKK-2 or p90_rsk_ protein, as indicated, was performed. Samples were also immunoprecipitated with an anti-IgG antibody and immunoblotted with HA or Flag as a negative control. (D) HEK 293 cells were treated for 2 h with 5 μM DOX or DMSO vehicle. WCEs (2 mg) were immunoprecipitated with an anti-p90_rsk_ antibody (i), an anti-IKK1 and -2 antibody (ii), or an anti-IgG antibody as a negative control. Following immunoprecipitation, immunoblotting of equal immunoprecipitated aliquots was performed with an anti-p90_rsk_ or an anti-IKK-2 antibody. Aliquots of nonimmunoprecipitated (no IP) WCEs (80 μg) were also subjected to immunoblotting with an anti-IKK-2 or anti p90_rsk_ antibody (bottom). (E) HEK 293 cells were transfected as described above with vectors directing expression of HA-p90_rsk_ or dominant negative mutant (HA-D205N) p90_rsk_ and Flag-tagged IKK-2 (Flag-IKK-2). Immunoprecipitation and immunoblotting were performed as described above. In addition, nonimmunoprecipitated WCEs (25 μg) were subjected to immunoblotting with antibodies against IKK-2 or actin (bottom).

FIG. 3.

FIG. 3.

p90_rsk_ mediates IKK complex and NF-κB activation by anthracyclines through association with the IKK-2 subunit. (A) (10)1 cells were treated at the indicated time points with 5 μM DOX or 5 μM AD 288 in the absence or presence of PD98059 (100 μM). Following immunoprecipitation (IP) with an antibody against p90_rsk_, a kinase assay using IκB-α-GST as the substrate was performed (top). An equal aliquot of each immunoprecipitant was subjected to immunoblotting (IB) as indicated (bottom) with an anti-p90_rsk_ antibody. ns, nonspecific. (B) HEK 293 cells were plated in triplicate in 96-well plates and transfected by lipofection with 50 ng of NF-κB-luciferase construct in the presence of the indicated amount of empty vector (pcDNA) or vectors directing expression of either the wild-type (wt) or dominant negative (D205N) p90_rsk_ gene. Following 24 h of treatment with 5 μM DOX, luciferase activity was determined as described in the legend of Fig. 1. Means and standard deviations are representative of three independent experiments carried out in triplicate. Bars represent standard deviations. (C) HEK 293 cells were transfected by lipofection with vectors directing expression of N-terminally HA-tagged p90_rsk_ (HA-p90_rsk_) or Flag-tagged IKK-2 (Flag-IKK-2). Transfected cells were treated for 2 h with 5 μM DOX or DMSO carrier solution. Following immunoprecipitation with an antibody (Ab) against Flag (i) or against HA (ii), immunoblotting with equal immunoprecipitated aliquots of either IKK-2 or p90_rsk_ protein, as indicated, was performed. Samples were also immunoprecipitated with an anti-IgG antibody and immunoblotted with HA or Flag as a negative control. (D) HEK 293 cells were treated for 2 h with 5 μM DOX or DMSO vehicle. WCEs (2 mg) were immunoprecipitated with an anti-p90_rsk_ antibody (i), an anti-IKK1 and -2 antibody (ii), or an anti-IgG antibody as a negative control. Following immunoprecipitation, immunoblotting of equal immunoprecipitated aliquots was performed with an anti-p90_rsk_ or an anti-IKK-2 antibody. Aliquots of nonimmunoprecipitated (no IP) WCEs (80 μg) were also subjected to immunoblotting with an anti-IKK-2 or anti p90_rsk_ antibody (bottom). (E) HEK 293 cells were transfected as described above with vectors directing expression of HA-p90_rsk_ or dominant negative mutant (HA-D205N) p90_rsk_ and Flag-tagged IKK-2 (Flag-IKK-2). Immunoprecipitation and immunoblotting were performed as described above. In addition, nonimmunoprecipitated WCEs (25 μg) were subjected to immunoblotting with antibodies against IKK-2 or actin (bottom).

FIG. 4.

FIG. 4.

p90_rsk_ is required for NF-κB activation. (A) HEK 293 cells were lipofected as described in the legend of Fig. 3 with vectors directing expression of HA-p90_rsk_ or dominant negative mutant (HA-D205N) p90_rsk_. Transfected cells were then treated for the indicated times with 5 μM DOX. WCEs (50 μg) were subjected to immunoblotting (IB) with an anti-IκB-α or actin antibody. (B) HEK 293 cells were transfected as described above and treated for 2 h with 5 μM DOX. WCEs were subjected to immunoblotting with an antibody that recognizes IKK-1 and -2 phosphorylated at serines 180 and 181, respectively (top). The same blot was also hybridized with an antibody against actin (bottom). (C) HEK 293 cells were transfected by lipofection with vectors directing expression of HA-tagged wild-type p90_rsk_ (HA-p90_rsk_) or the dominant negative mutant (HA-D205N) p90_rsk_. After 24 h, transfected cells were treated for 2 h with 5 μM DOX or DMSO carrier solution. Following immunoprecipitation (IP) with an antibody against p90_rsk_, a kinase assay using GST-IKK-2 as the substrate was performed (top). The immunoprecipitants were also subjected to immunoblotting with the anti-HA antibody (bottom). (D) WCEs of HEK 293 cells that had been incubated for 2 h with 5 mM DOX, AD 288, or DMSO carrier solution were immunoprecipitated with an antibody specific for p90_rsk_. Subsequently, immunoprecipitants were subjected to kinase assay as described above. Equal aliquots of the immunoprecipitants were subjected to immunoblotting with an anti-p90_rsk_ antibody. (E) HEK 293 cells were lipofected with 100 nM siRNA specific for p90_rsk_ (si-p90_rsk_) or 100 nM siRNA nonspecific siRNA control (si-cont). After 48 h of transfection, cells were treated for 2 h with 5 μM DOX or DMSO carrier solution and WCEs were subjected to immunoblotting with a p90_rsk_-specific antibody (top), a phospho-specific IKK-1 and -2 antibody (middle), or an antibody against actin (bottom).

FIG. 5.

FIG. 5.

ATM is required for activation of NF-κB and ERK by DOX. (A) Wild-type (GM00637) and A-T (GM09607) fibroblasts were treated for the indicated times with 5 μM DOX. Alternatively, cells were treated for 30 min with 20 ng of TNF-α/ml or bovine serum albumin carrier solution. NF-κB DNA binding activity was determined by EMSA using as probe the URE-κβ or the Oct-1 oligonucleotide, as described in the legend of Fig. 1. (B) GM00637 cells were infected for 24 h with 10 PFU of adenovirus (ad) constructs directing expression of wild-type (wt) IKK-2 or dominant negative IKK-2 K>M. Subsequently, cells were treated for 5 h with 5 μM DOX, 5 μM AD 288, or DMSO carrier solution. Nuclear extracts (5 μg) were subjected to EMSA. (C) GM00637 or GM09607 cells were treated for 5 h with 5 μM DOX, 5 μM AD 288, or DMSO carrier solution. Nuclear extracts were subjected to EMSA. (D) GM00637 (wt) or GM09607 (A-T) cells were treated for the indicated times with 5 μM DOX or 5 μM AD 288. WCEs (40 μg) were subjected to immunoblotting (IB) with an antibody that recognizes phospho-ERK species (pERK1,2) or total ERK (totERK1,2). As a control for equal loading, the same filters were hybridized with an antibody against actin.

FIG. 6.

FIG. 6.

ATM promotes NF-κB activation in response to DOX treatment through activation of the MEK/ERK pathway. (A) (10)1 cells were treated for 5 h with 5 μM DOX, 5 μM AD 288, or DMSO carrier solution in the absence or presence of caffeine (5 mM), and nuclear extracts were subjected to EMSA. (B) GM00637 (wild-type [wt]) cells were treated for 5 h with 5 μM DOX or DMSO carrier solution in the absence or presence of wortmannin (wort.; 50 nM or 50 μM). Nuclear extracts were subjected to EMSA. (C) (10)1 cells were treated for 5 h with 5 μM DOX or DMSO carrier solution in the absence or presence of caffeine (5 mM), wortmannin (5 μM), or UO126 (20 μM). Immunoblotting (IB) was performed with an antibody that recognizes phospho-ERK species (pERK1,2) or total ERK (totERK1,2). (D) A-T (GM09607) fibroblasts were infected at a multiplicity of infection (MOI) of 1 for 48 h with the HGC-ATM vector. Subsequently, cells were treated for the indicated times with 5 μM DOX. WCEs (800 μg) were immunoprecipitated (IP) with an anti-Flag antibody (Ab) and immunoblotted with an anti-ATM antibody or an antibody that recognizes autophosphorylated ATM at serine 1981. (E) A-T (GM09607) fibroblasts were infected at MOI of 1 for 48 h with the HGCX or the HGC-ATM vector. Subsequently, cells were treated for 5 h with 5 μM DOX or DMSO carrier solution. Nuclear extracts (5 μg) were subjected to EMSA. Alternatively WCEs (40 μg) from the same experiment were subjected to immunoblotting with an antibody that recognizes phospho-ERK species (pERK1,2) or total ERK (totERK1,2). (F) GM09607 (A-T) fibroblasts were plated in triplicate in 96-well plates and transfected by lipofection with 50 ng of the NF-κB-luciferase construct in the presence of 25 ng of pcDNA3-Flag-ATM (wt-ATM) or pcDNA3-Flag-KD-ATM (KD-ATM) expression vectors and, as an internal control, a Renilla luciferase expression plasmid. Total DNA concentration was adjusted to 150 ng with backbone vector (pcDNA). Following 24 h of treatment with 5 μM DOX in the absence or presence of PD98059 (50 μM), luciferase activity was measured and expressed as induction relative to that of DMSO-treated cells, which was set at 1. Means and standard deviations (bars) are representative of three independent experiments carried out in triplicate.

FIG. 7.

FIG. 7.

DNA-PKcs mediates NF-κB activation by AD 288. (A and B) GM09607 (A-T) fibroblasts were treated for 5 h with 5 μM AD 288 or DMSO in the presence or absence of wortmannin (wort.; 50 nM or 50 μM), MG132 (30 μM), or PD98059 (50 μM), and nuclear extracts were subjected to EMSA. (C) Wild-type CHO AA8 and DNA-PKcs−/− CHO V-3 cells were treated with 5 μM AD 288 for the indicated times, and nuclear extracts were subjected to EMSA. PD, PD98059. (D) AA8, V-3, and V-3F18 cells that express ectopic DNA-PKcs were treated with 5 μM AD 288 for the indicated times, and nuclear extracts were subjected to EMSA. (E) V-3F18 cells were treated for 5 h with 5 μM AD 288 or DMSO in the presence or absence of wortmannin (50 nM), PD98059 (50 μM), or caffeine (5 mM), and nuclear extracts were subjected to EMSA.

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