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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell cycle checkpoint, a major genomic surveillance mechanism, is an important step in maintaining genomic stability and integrity in response to environmental stresses. Using cells derived from human bronchial epithelial cells, we demonstrate that NF-kappaB and c-Jun N-terminal kinase (JNK) reciprocally regulate arsenic trioxide (arsenite)-induced, p53-independent expression of GADD45 protein, a cell cycle checkpoint protein that arrests cells at the G(2)/M phase transition. Inhibition of NF-kappaB activation by stable expression of a kinase-mutated form of IkappaB kinase caused increased and prolonged induction of GADD45 by arsenite. In contrast, the induction of GADD45 by arsenite was transient and less potent in cells where the NF-kappaB activation pathway was normal. Analysis of the cell cycle profile by flow cytometry indicated that NF-kappaB inhibition potentiates arsenite-induced G(2)/M cell cycle arrest. Abrogation of JNK activation, on the other hand, decreased GADD45 expression induced by arsenite, suggesting a role for JNK activation in GADD45 induction. These results indicate a molecular mechanism by which NF-kappaB and JNK may differentially contribute to cell cycle regulation in response to arsenite.
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PMID:Opposite effect of NF-kappa B and c-Jun N-terminal kinase on p53-independent GADD45 induction by arsenite. 1115 Mar 9

Hepatitis B virus produces chronic infections of the liver leading to cirrhosis and hepatocellular carcinoma. The X protein of hepatitis B virus (HBx) is a multifunctional protein that can interact with p53 but can also influence a variety of signal transduction pathways within the cell. In most instances this small viral protein favors cell survival and probably initiates hepatocarcinogenesis. HBx upregulates the activity of a number of transcription factors including NF-kappa B, AP-1, CREB, and TBP. However, the majority of HBx is localized to the cytoplasm where it interacts with and stimulates protein kinases such as protein kinase C, Janus kinase/STAT, IKK, PI-3-K, stress-activated protein kinase/Jun N-terminal kinase, and protein kinase B/Akt. This small viral protein can localize to the mitochondrion. HBx may act as an adaptor or kinase activator to influence signal transduction pathways. This review will attempt to analyze the involvement of HBx in signal transduction pathways during hepatitis B viral infections and hepatocellular carcinoma development.
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PMID:X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. 1132 2

ML-1 human myeloblastic leukemia cells, suspended in serum-depleted medium, proliferate when the insulin-like growth factor-1 (IGF-1) and transferrin (Tf) are supplied, but differentiate to monocytes when these factors are replaced by the tumor necrosis factor-alpha (TNF-alpha). Induction of differentiation, but not of proliferation, involved the selective activation of diverse members of the NF-kappaB family of proteins. In differentiation-induced cells, NF-kappaB (p65) was translocated from the cytoplasm to the nucleus, whereas NF-kappaB (p75) remained localized to the cytoplasm. In contrast, NF-kappaB (p52) was present in the nuclei of proliferation- as well as of differentiation-induced ML-1 cells. The differentiation-specific translocation of NF-kappaB (p65) from the cytoplasm to the nucleus was mediated by an increase in the level of NIK, the NF-kappaB-inducing kinase which, through phosphorylation of IkappaB kinase alpha (Ikappakalpha), causes a decrease in the level of IkappaBalpha, allowing p65 to move from the cytoplasm to the nucleus. The p52/p65 heterodimer formed in the nucleus, bound specifically to the promoter of the tumor suppressor protein p53, effecting a 25 to 30-fold increase in the level of this protein. As we reported previously (Li et al, Cancer Res 1998; 58: 4282-4287), that increase led to the decreased expression of proliferating cell nuclear antigen (PCNA) and to the loss of proliferation-associated DNA synthesis. The ensuing uncoupling of growth from differentiation was followed by the initiation of the monocyte-specific differentiation program.
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PMID:NF-kappaB (p65/RelA) as a regulator of TNFalpha-mediated ML-1 cell differentiation. 1136 42

Growth arrest and DNA damage-inducible protein 45alpha (GADD45alpha) is an important cell cycle checkpoint protein that arrests cells at G2/M phase by inhibiting the activity of G2-specific kinase, cyclin B/p34cdc2. We report here that arsenite induces GADD45alpha expression in a p53-independent fashion and that this GADD45alpha induction by arsenite is regulated by NF-kappaB and c-Jun-N-terminal kinase (JNK) oppositely. In human bronchial epithelial cells overexpressing a kinase-mutated form of IkappaB kinase beta (IKKbeta-KM), the activation of NF-kappaB was inhibited. However, the G2/M cell cycle arrest and expression of GADD45alpha was substantially enhanced in response to arsenite in these cells. Expression of a dominant-negative mutant of SEK1 that blocks JNK activation decreased arsenite-induced GADD45alpha expression. Analysis of GADD45alpha expression in both wild-type and p53-/- fibroblasts indicated that the induction of GADD45alpha by arsenite was independent of the status of p53 protein.
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PMID:Contrasting roles of NF-kappaB and JNK in arsenite-induced p53-independent expression of GADD45alpha. 1142 7

Sanglifehrin A belongs to a novel family of immunophilin-binding ligands. Sanglifehrin A is similar to cyclosporin A in that it binds to cyclophilins. Unlike cyclosporin A, however, the cyclophilin-sanglifehrin A complex has no effect on the calcium-dependent protein phosphatase calcineurin. It has been previously shown that sanglifehrin A specifically blocks T cell proliferation in response to interleukin 2 by inhibiting the appearance of cell cycle kinase activity cyclinE-Cdk2. How sanglifehrin A treatment leads to the cell cycle blockade has remained unknown. We report that sanglifehrin A is capable of activating the tumor suppressor gene p53 at the transcription level, leading to up-regulation of p21 that then binds and inhibits the cylcinE-Cdk2 complex. Further analysis of different elements in the p53 promoter showed that sanglifehrin A activates p53 transcription primarily through the activation of the transcription factor NFkappaB by activating IkappaB kinase in a manner that is similar to several genotoxic agents. Unlike other genotoxic drugs, sanglifehrin A does not cause DNA damage, making it a unique natural product that is capable of activating the NFkappaB signaling pathway without affecting DNA.
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PMID:Inhibition of cell cycle progression by the novel cyclophilin ligand sanglifehrin A is mediated through the NFkappa B-dependent activation of p53. 1155 53

Although c-Jun NH(2)-terminal kinase (JNK) is activated by treatment with therapeutic agents, the biologic sequelae of inhibiting constitutive activation of JNK has not yet been clarified. In this study, we examine the biologic effect of JNK inhibition in multiple myeloma (MM) cell lines. JNK-specific inhibitor SP600125 induces growth inhibition via induction of G1 or G2/M arrest in U266 and MM.1S multiple myeloma cell lines, respectively. Neither exogenous IL-6 nor insulin-like growth factor-1 (IGF-1) overcome SP600125-induced growth inhibition, and IL-6 enhances SP600125-induced G2/M phase in MM.1S cells. Induction of growth arrest is mediated by upregulation of p27(Kip1), without alteration of p53 and JNK protein expression. Importantly, SP600125 inhibits growth of MM cells adherent to bone marrow stromal cells (BMSCs). SP600125 induces NF-kappaB activation in a dose-dependent fashion, associated with phosphorylation of IkappaB kinase alpha (IKKalpha) and degradation of IkappaBalpha. In contrast, SP600125 does not affect phosphorylation of STAT3, Akt, and/or ERK. IKK-specific inhibitor PS-1145 inhibits SP600125-induced NF-kappaB activation and blocks the protective effect of SP600125 against apoptosis. Our data therefore demonstrate for the first time that inhibiting JNK activity induces growth arrest and activates NF-kappaB in MM cells.
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PMID:Biologic sequelae of c-Jun NH(2)-terminal kinase (JNK) activation in multiple myeloma cell lines. 1464 74

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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PMID: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. 1496 65

Previous studies have shown that DNA damage-evoked death of primary cortical neurons occurs in a p53 and cyclin-dependent kinase-dependent (CDK) manner. The manner by which these signals modulate death is unclear. Nuclear factor-kappaB (NF-kappaB) is a group of transcription factors that potentially interact with these pathways. Presently, we show that NF-kappaB is activated shortly after induction of DNA damage in a manner independent of the classic IkappaB kinase (IKK) activation pathway, CDKs, ATM, and p53. Acute inhibition of NF-kappaB via expression of a stable IkappaB mutant, downregulation of the p65 NF-kappaB subunit by RNA interference (RNAi), or pharmacological NF-kappaB inhibitors significantly protected against DNA damage-induced neuronal death. NF-kappaB inhibition also reduced p53 transcripts and p53 activity as measured by the p53-inducible messages, Puma and Noxa, implicating the p53 tumor suppressor in the mechanism of NF-kappaB-mediated neuronal death. Importantly, p53 expression still induces death in the presence of NF-kappaB inhibition, indicating that p53 acts downstream of NF-kappaB. Interestingly, neurons cultured from p65 or p50 NF-kappaB-deficient mice were not resistant to death and did not show diminished p53 activity, suggesting compensatory processes attributable to germline deficiencies, which allow p53 activation still to occur. In contrast to acute NF-kappaB inhibition, prolonged NF-kappaB inhibition caused neuronal death in the absence of DNA damage. These results uniquely define a signaling paradigm by which NF-kappaB serves both an acute p53-dependent pro-apoptotic function in the presence of DNA damage and an anti-apoptotic function in untreated normal neurons.
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PMID:Nuclear factor-(kappa)B modulates the p53 response in neurons exposed to DNA damage. 1504 35

Nuclear factor kappaB (NF-kappaB) has been implicated in inducible chemoresistance against anthracyclines. In an effort to improve the cytotoxicity of anthracyclines while reducing their cardiotoxic effects, we have developed a novel class of extranuclear-localizing 14-O-acylanthracyclines that bind to the phorbol ester/diacylglycerol-binding C1b domain of conventional and novel protein kinase C (PKC) isoforms, thereby promoting an apoptotic response. Because PKCs have been shown to be involved in NF-kappaB activation, in this report, we determined the mechanism of NF-kappaB activation by N-benzyladriamycin-14-valerate (AD 198) and N-benzyladriamycin-14-pivalate (AD 445), two novel 14-O-acylanthracylines. We show that the induction of NF-kappaB activity in response to drug treatment relies on the activation of PKC-delta and NF-kappaB-activating kinase (NAK), independent of ataxia telengectasia mutated and p53 activities. In turn, NAK activates the IKK complex through phosphorylation of the IKK-2 subunit. We find that neither NF-kappaB activation nor ectopic expression of Bcl-X(L) confers protection from AD 198-induced cell killing. Overall, our data indicate that activation of novel PKC isoforms by cytoplasmic-targeted 14-O-acylanthracyclines promotes an apoptotic response independent of DNA damage, which is unimpeded by inducible activation of NF-kappaB.
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PMID:Circumvention of nuclear factor kappaB-induced chemoresistance by cytoplasmic-targeted anthracyclines. 1504 34

Both pro- and antiapoptotic activities of NF-kappaB transcription factor have been observed; however, less is known about the mechanism by which NF-kappaB induces apoptosis. To elucidate how NF-kappaB regulates proapoptotic signaling, we performed functional analyses using wild-type, ikk1(-/-), ikk2(-/-), rela(-/-) murine fibroblasts, MDAPanc-28/Puro, MDAPanc-28/IkappaBalphaM, and HCT116/p53(+/+) and HCT116/p53(-/-) cells with investigational anticancer agent doxycycline as a superoxide inducer for generating apoptotic stimulus. In this report, we show that doxycycline increased superoxide generation and subsequently activated NF-kappaB, which in turn up-regulated p53 expression and increased the stability and DNA binding activity of p53. Consequently, NF-kappaB-dependent p53 activity induced the expression of p53-regulated genes PUMA and p21(waf1) as well as apoptosis. Importantly, lack of RelA, IKK, and p53 as well as expression of a dominant negative IkappaBalpha (IkappaBalphaM) inhibited NF-kappaB-dependent p53 activation and apoptosis. The doxycycline-induced NF-kappaB activation was not inhibited in HCT116/p53(-/-) cells. Our results demonstrate that NF-kappaB plays an essential role in activation of wild-type p53 tumor suppressor to initiate proapoptotic signaling in response to overgeneration of superoxide. Thus, these findings reveal a mechanism of NF-kappaB-regulated proapoptotic signaling.
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PMID:Stabilization of p53 is a novel mechanism for proapoptotic function of NF-kappaB. 1510 62


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