Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear factor kappaB (NF-kappaB) is a transcription factor that controls the expression of many cellular and viral genes. The p65 (RelA) subunit plays a critical role as a transcriptional activator and recent observations have highlighted its role in the control of apoptosis. Here we report that 53BP2, a protein previously identified by interaction with wild type p53 and Bcl-2, also binds to p65 in a yeast two-hybrid system. This specific interaction was confirmed by pull-down assay in vitro and by a mammalian two-hybrid assay in vivo. We observed that full-length 53BP2 fused to GFP had a punctate distribution in cytoplasm, predominantly in perinuclear region whereas the N-terminal 53BP2 localized in cytoplasm and C-terminal 53BP2 localized in the nucleus. Furthermore, we found that overexpression of GFP-53BP2 induced apoptosis in transiently transfected cells. Neither the N-terminal nor the C-terminal of 53BP2 fused to GFP induced cell death. Interestingly, co-transfection with a p65 expression plasmid significantly inhibited 53BP2-induced cell death. The previous findings that 53BP2 bound to p53 and Bcl-2 together with our present observations suggest that 53BP2 may play a central role in the regulation of apoptosis and cell growth.
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PMID:NF-kappaB subunit p65 binds to 53BP2 and inhibits cell death induced by 53BP2. 1049 67

p53 is known to be recruited in response to DNA-damaging genotoxic stress and plays an important role in maintaining the integrity of the genome. In the present study, the effect of a potent lung cancer carcinogen, benzo[a]pyrene (B[a]P) on p53 expression was investigated. We showed that exposure of A549 and NIH 3T3 cells to B[a]P resulted in an increase in p53 mRNA levels and in p53 promoter activation, indicating that B[a]P-induced p53 expression is partly regulated at the transcriptional level. The p53 promoter region which extends from -58 to -43, overlapping the kappaB motif, is essential for both the p53 basal promoter activity and p53 promoter activation induced by B[a]P. Nuclear factor kappaB (NF-kappaB) proteins have been revealed to be activated in B[a]P-induced p53 expression. Activated NF-kappaB complexes were shown to contain predominantly p50 and p65 subunit components in A549 cells and p65 subunit in NIH 3T3 cells. In addition, the overexpression of IkappaBalpha completely inhibited NF-kappaB activation, p53 promoter transactivation and the stimulatory effect on p53 transcription induced by B[a]P. We therefore conclude that B[a]P transcriptionally activates the human p53 gene through the induction of NF-kappaB activity.
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PMID:Benzo[a]pyrene activates the human p53 gene through induction of nuclear factor kappaB activity. 1057 10

Transcriptional activation domains share little sequence homology and generally lack folded structures in the absence of their targets, aspects that have rendered activation domains difficult to characterize. Here, a combination of biochemical and nuclear magnetic resonance experiments demonstrates that the activation domain of the tumor suppressor p53 has an FXXPhiPhi motif (F, Phe; X, any amino acids; Phi, hydrophobic residues) that folds into an alpha-helix upon binding to one of its targets, hTAF(II)31 (a human TFIID TATA box-binding protein-associated factor). MDM2, the cellular attenuator of p53, discriminates the FXXPhiPhi motif of p53 from those of NF-kappaB p65 and VP16 and specifically inhibits p53 activity. Our studies support the notion that the FXXPhiPhi sequence is a general alpha-helical recognition motif for hTAF(II)31 and provide insights into the mechanistic basis for regulation of p53 function.
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PMID:The alpha-helical FXXPhiPhi motif in p53: TAF interaction and discrimination by MDM2. 1061 Dec 93

The present study evaluated whether nuclear factor-kappaB (NF-kappaB) activation contributes to the apoptotic-like death of striatal neurons induced by kainic acid (KA) receptor stimulation. Intrastriatally infused KA (1.25-5.0 nmol) produced substantial neuronal loss as indicated by an 8-73% decrease in 67-kDa glutamic acid decarboxylase (p<0.05). KA (1.25-5.0 nmol) elicited internucleosomal DNA fragmentation that was inhibited by the AMPA/KA receptor antagonist NBQX (1,2,3,4-tetrahydro-6-nitro-2,3-dibenzo[f]quinoxaline-7-sulfonamide) but not by the NMDA receptor antagonist MK-801. A decrease in IkappaB-alpha protein levels, which was accompanied by an increase in NF-kappaB binding activity, was found from 6 to 72 h after KA (2.5 nmol) infusion. NF-kappaB was composed mainly of p65 and c-Rel as revealed by supershift assay. In addition, c-Myc and p53 increased from five- to sevenfold from 24 to 72 h after KA (2.5 nmol) administration. Immunohistochemistry revealed high levels of c-Myc and p53 immunoreactivity, mainly in medium-sized striatal neurons. Pretreatment with the cell-permeable recombinant peptide NF-kappaB SN50 (5-20 microg) blocked NF-kappaB nuclear translocation, but had no effect on AP-1 binding. NF-kappaB SN50 also inhibited the KA-induced up-regulation of c-Myc and p53, as well as internucleosomal DNA fragmentation. The apoptotic-like destruction of rat striatal neurons induced by KA receptor stimulation thus appears to involve biochemical mechanisms similar to those mediating the excitotoxic response to NMDA receptor stimulation. The present results provide additional support for the view that NF-kappaB activation contributes to c-Myc and p53 induction and subsequent apoptosis in an excitotoxic model of Huntington's disease.
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PMID:Kainic acid-induced apoptosis in rat striatum is associated with nuclear factor-kappaB activation. 1064 16

p53 plays a key role in guarding cells against DNA damage and transformation. We previously demonstrated that the human T-cell lymphotropic virus type 1 (HTLV-1) Tax can inactivate p53 transactivation function in lymphocytes. The present study demonstrates that in T cells, Tax-induced p53 inactivation is dependent upon NF-kappaB activation. Analysis of Tax mutants demonstrated that Tax inactivation of p53 function correlates with the ability of Tax to induce NF-kappaB but not p300 binding or CREB transactivation. The Tax-induced p53 inactivation can be overcome by overexpression of a dominant IkappaB mutant. Tax-NF-kappaB-induced p53 inactivation is not due to p300 squelching, since overexpression of p300 does not recover p53 activity in the presence of Tax. Further, using wild-type and p65 knockout mouse embryo fibroblasts (MEFs), we demonstrate that the p65 subunit of NF-kappaB is critical for Tax-induced p53 inactivation. While Tax can inactivate endogenous p53 function in wild-type MEFs, it fails to inactivate p53 function in p65 knockout MEFs. Importantly, Tax-induced p53 inactivation can be restored by expression of p65 in the knockout MEFs. Finally, we present evidence that phosphorylation of serines 15 and 392 correlates with inactivation of p53 by Tax in T cells. This study provides evidence that the divergent NF-kappaB proliferative and p53 cell cycle arrest pathways may be cross-regulated at several levels, including posttranslational modification of p53.
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PMID:Inactivation of p53 by human T-cell lymphotropic virus type 1 Tax requires activation of the NF-kappaB pathway and is dependent on p53 phosphorylation. 1077 27

Alterations in the cell division:cell death ratio induce multiple autoimmune and transformation processes. Phosphoinositide 3-kinase (PI3K) controls cell division and cell death in vitro, but its effect on the function of the cellular immune system and on tumor formation in mammals is poorly characterized. Here we show that transgenic mice expressing in T lymphocytes an active form of PI3K derived from a thymic lymphoma, p65(PI3K), developed an infiltrating lymphoproliferative disorder and autoimmune renal disease with an increased number of T lymphocytes exhibiting a memory phenotype and reduced apoptosis. This pathology was strikingly similar to that described in mice exhibiting heterozygous loss of the tumor suppressor PTEN, a lipid and protein phosphatase. We show that overexpression of PTEN selectively blocks p65(PI3K)-induced 3T3 fibroblast transformation. Moreover, the early development of T cell lymphomas in p65(PI3K) Tg p53(-/-) mice indicated that PI3K contributes to tumor development. These observations demonstrate that constitutive activation of PI3K extends T cell survival in vivo, affects T cell homeostasis, and contributes to tumor generation, supporting a model in which selective increases in one type of PTEN substrate, the PI3K-derived lipid products, induce tumorigenesis. PI3K thus emerges as a potential target in autoimmune disease and cancer therapy.
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PMID:Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo. 1078 43

Paraffin-embedded tissue slides from 88 infiltrating ductal breast carcinoma were examined by immunohistochemistry technique with the use of monoclonal antibody against human p65 antigen and polyclonal antibody against p65-like protein present in fetal bovine serum. Immunohistochemical analysis of expression of growth factor receptors (EGFR), protein product of oncogene c-erb B2 as well as protein product of mutated anti-oncogene p53 was also done. It was established that there is no correlation between p65 and c-erbB2, EGFR or p53 expression. In low differentiated tumors (grade III) high p53 index and high EGFR and c-erbB2 expression was connected with low p65 expression. The lack of c-erbB2 and EGFR and low p53 expression was combined usually with high p65 oncoprotein levels.
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PMID:Immunohistochemical analysis of expression of a 65 kDa oncofetal protein (p65), epidermal growth factor receptor (EGFR), oncogene c-erb B2 and tumor suppressor gene p53 protein products in breast cancer patients. 1087 Jun 81

The p53 protein plays a pivotal role in transmitting signals from many forms of genotoxic stress to genes and factors that control aspects of the cell cycle and death. Although mutated in approximately 60% of all human cancers, only a minority of human T-lymphotropic virus type 1 (HTLV-1)-transformed cells carry p53 mutations. Nevertheless, the p53 protein in HTLV-1-transformed cells is functionally inactive. We have previously demonstrated that the HTLV-1 Tax protein can inhibit p53 trans-activation function. Tax does not accomplish this by directly binding to p53, but rather by a unique mechanism that includes constitutive phosphorylation of p53 at Ser-15 and Ser-392. Analysis of Tax mutants in lymphocytes demonstrates that Tax-induced p53 inhibition correlates with the ability of Tax to activate NF-kappaB, but not p300 binding or CREB trans-activation. Consistent with these results, expression of the I-kappaBalpha(S32,36A) mutant that blocks NF-kappaB activation blocks Tax-mediated p53 inhibition. We further demonstrate the importance of Tax activation of NF-kappaB in p53 inhibition, using p65 knockout (KO) mouse embryo fibroblasts (MEFs). In the absence of p65 Tax could not inhibit p53. Tax does activate IKKbeta in the p65 KO MEFs, indicating that prenuclear events of NF-kappaB activation are not sufficient for Tax-mediated p53 inhibition, but rather NF-kappaB transcriptional activation is critical. Importantly, using phosphospecific antibodies, we demonstrate that phosphorylation of p53 at Ser-15 and Ser-392 correlates with Tax-mediated inhibition. In addition, mutation of p53 at Ser-15 and Ser-392 to alanines renders p53 resistant to Tax inhibition. This report reviews p53 inhibition by Tax and presents our current model.
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PMID:Insights into the molecular mechanism of p53 inhibition by HTLV type 1 Tax. 1108 Aug 8

Neoplastically transformed mouse and human keratinocytes elevate transactivation of both activator protein 1 (AP-1) and nuclear factor kappaB (NFkappaB) transcription factors. The present study addresses the question of whether elevated NFkappaB in addition to elevated AP-1-dependent gene expression is necessary for maintaining the tumor cell phenotype. When a tetracycline-regulatable dominant-negative c-jun (TAM67, having a truncated transactivation domain) was expressed in tumorigenic human keratinocytes, AP-1- and NFkappaB- but not p53-dependent reporter activity was inhibited by 40-60%. Tumor phenotype, as measured by anchorage-independent growth, was inhibited by 90%. Neither AP-1/NFkappaB activation nor expression of tumor phenotype was inhibited in TAM67-harboring keratinocytes under noninducing conditions. Electrophoretic mobility shift analysis showed that induction of TAM67 expression slightly increased AP-1- but reduced NFkappaB DNA-binding activity. Immunoprecipitation showed that TAM67 interacted in keratinocyte nuclei with NFkappaB p65, suggesting that inhibition of NFkappaB by TAM67 is mediated by direct protein-protein interactions, possibly producing decreased binding to DNA or inactivating p65. To analyze the putative effector genes that may be targeted by TAM67, expression of genes responsive to AP-1 or NFkappaB was measured by reverse transcriptase-polymerase chain reaction in TAM67 transfectants with or without TAM67 induction. Induction of TAM67 inhibited or reduced the expression of collagenase I, stromelysin I (AP-1 responsive), and interleukins 1 and 6 (NFkappaB responsive). These results indicate that genes controlled by NFkappaB and by AP-1 may be transformation-relevant targets of TAM67 and that TAM67 may inhibit NFkappaB activation through direct interaction with NFkappaB p65. Moreover, the findings provide proof for the principle of using inducible TAM67 as a gene therapy to suppress tumor phenotype in human carcinoma cells.
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PMID:Induced expression of dominant-negative c-jun downregulates NFkappaB and AP-1 target genes and suppresses tumor phenotype in human keratinocytes. 1110 61

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


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