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)

Neutrophil lactoferrin (Lf) was previously shown to act as a transcriptional activator in various mammalian cells. Here, we describe that Lf specifically transactivates the p53 tumor suppressor gene through the activation of nuclear factor-kappaB (NF-kappaB) and consequently regulates p53-responsive oncogenes. In HeLa cervical carcinoma cells stably expressing Lf (HeLa-Lf), expression of mdm2 and p21waf1/cip1 as well as p53 was greatly enhanced. Transient expression of Lf also markedly transactivates transcription of a p53 promoter-driven reporter and NF-kappaB-driven reporters in various mammalian cells. However, mutation of the NF-kappaB site or treatment with an NF-kappaB inhibitor abrogated the transactivation, suggesting that NF-kappaB should play an essential role in the Lf-induced transactivation. Increased binding activity and nuclear translocation of p65 in response to Lf strongly support these findings. Furthermore, Lf-mediated NF-kappaB activation is diminished in IKKalpha- or IKKbeta-deficient mouse embryonic fibroblast cells. The activation of both IKKs and NF-kappaB by Lf is over-ridden by the expression of dominant-negative mutants of NIK, MEKK1, IKKalpha and IKKbeta. Collectively, we conclude that overexpressed Lf directly relays signals to upstream components responsible for NF-kappaB activation, thereby leading to the activation of NF-kappaB target genes.
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PMID:Neutrophil lactoferrin upregulates the human p53 gene through induction of NF-kappaB activation cascade. 1537 4

The physical and functional interaction between the transcription factor p53 and its negative regulatory partner protein Hdm2 (Mdm2 in mouse) is a key point of convergence of multiple signaling pathways that regulates cell proliferation and survival. hdm2 mRNA transcription is induced by p53, forming the basis of an auto-regulatory feedback loop. Growth and survival factor-activated Ras-Raf-MEK-ERK signaling can also regulate Hdm2 expression independently of p53, contributing to the pro-survival effect of these factors. In murine fibroblasts, this occurs through the regulation of mdm2 mRNA transcription. Here we show that, in human breast cancer epithelial cells, MEK-dependent regulation of Hdm2 expression also occurs at a post-transcriptional level. Pharmacological blockade of MEK activity in T47D cells inhibits Hdm2 protein synthesis by 80-90%. This occurs in the absence of changes in the expression of the major hdm2-P1 mRNA transcript and only an approximately 40% reduction in hdm2-P2 transcript levels. The amounts of both transcripts that are associated with polyribosomes and are, hence, being actively translated are reduced by >80% by the MEK inhibitor, U0126. We show here that this is due to the inhibition of hdm2 mRNA export from the nucleus when MEK activity is inhibited. In MCF-7 breast cancer cells that express wild-type p53, Hdm2 is required to suppress p53-dependent transcription when MEK kinase is active. Regulation of the nuclear export of hdm2 mRNA provides, therefore, a mechanism whereby mitogen-stimulated cells avoid p53-dependent cell cycle arrest or apoptosis by maintaining the dynamic equilibrium of the Hdm2-p53 feedback loop.
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PMID:MEK-ERK signaling controls Hdm2 oncoprotein expression by regulating hdm2 mRNA export to the cytoplasm. 1572 37

Myocardial ischemia/reperfusion (IR) induces myocyte apoptosis, and the pro-apoptotic/tumor suppressor protein p53 may contribute to this process. However, the signaling mechanism by which IR induces p53 activation remains largely unknown. Here, we show that MEKK1 undergoes proteolytic cleavage in a caspase-3 dependent manner in both in vivo and in vitro models of ischemic injury. Overexpression studies both in vivo and in vitro indicated that the caspase-3 mediated cleavage of MEKK1 promotes phosphorylation and transcriptional activity of p53. In addition, caspase-3 inhibited the ability of the wild-type full-length form of MEKK1 to activate ATF2, suggesting that caspase-3, by way of proteolytic cleavage, abrogates the ability of MEKK1 to signal JNK. We propose that IR induces caspase-3 mediated proteolytic cleavage of MEKK1 and promotes p53 transcriptional activity via JNK-independent mechanisms, which in turn may contribute to pathological insults associated with IR injury, such as myocyte apoptosis.
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PMID:Caspase-3 mediated cleavage of MEKK1 promotes p53 transcriptional activity. 1660 Feb 92

In the present study, we show that E2Fs (E2 promoter-binding factors) regulate the expression of ASK-1 (apoptosis signal-regulating kinase 1), which encodes a mitogen-activated protein kinase kinase kinase, also known as MAP3K5. Its mRNA expression is cell-cycle-regulated in human T98G cells released from serum starvation. Moreover, overexpression and RNA interference experiments support the requirement of endogenous E2F/DP (E2F dimerization partner) activity for ASK-1 expression. Characterization of the human ASK-1 promoter demonstrates that the -95/+11 region is critical for E2F-mediated up-regulation. Chromatin immunoprecipitation assays show that E2F1-E2F4 are bound in vivo to the ASK-1 promoter in cycling cells, probably through a non-consensus E2F-binding site located 12 bp upstream of the transcription start site. Mutation of this site completely abolishes the ASK-1 promoter response to E2Fs as well as the E2F1 binding in electrophoretic mobility-shift experiments. Our results indicate that E2Fs modulate the expression of ASK-1 and suggest that some of the cellular functions of ASK-1 may be under the control of E2F transcription factors. Moreover, the up-regulation of ASK-1 may also favour the p53-independent E2F1 apoptotic activity.
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PMID:ASK-1 (apoptosis signal-regulating kinase 1) is a direct E2F target gene. 1651 85

Cyclooxygenase-2 (COX-2) overexpression has been linked to cell survival, transformation, and hyperproliferation. We examined the regulation of the tumor suppressor gene p53 and p53 target genes by prostaglandin E(2) (PGE(2)) in human synovial fibroblasts (HSF). PGE(2) induced a time-dependent increase in p53 Ser(15) phosphorylation, with no discernible change in overall p53 levels. PGE(2)-dependent Ser(15) phosphorylation was apparently mediated by activated p38 MAP kinase as SB202190, a p38 kinase inhibitor, blocked the response. Overexpression of a MKK3 construct, but not MKK1, stimulated SB202190-sensitive p53 Ser(15) phosphorylation. PGE(2)-stimulated [phospho-Ser(15)]p53 transactivated a p53 response element (GADD45)-luciferase reporter in transiently transfected HSF (SN7); the effect was compromised by overexpression of a dominant-negative mutant (dnm) of p53 or excess p53S15A expression plasmid but mimicked by a constitutively active p53S15E expression construct. PGE(2), wtp53 expression in the presence of PGE(2), and p53S15E suppressed steady-state levels of MEKK1-induced MMP-1 mRNA, effects nullified with co-transfection of p53 dnm or p53S15A. MEKK1-induced MMP-1 promoter-driven luciferase activity was largely dependent on a c/EBPbeta-NF-kappaB-like enhancer site at -2008 to -1972 bp, as judged by deletion and point mutation analyses. PGE(2), overexpression of p53wt with PGE(2), or p53S15E abolished the MEKK1-induced MMP-1 promoter luciferase activity. Gel-shift/super gel-shift analyses identified c/EBPbeta dimers and c/EBPbeta/NF-kappaB p65 heterodimers as binding species at the apparent site of MEKK1-dependent transactivation. PGE(2)-stimulated [phospho-Ser(15)]p53 abrogated the DNA binding of c/EBPbeta dimers and c/EBPbeta/NF-kappaB p65 heterodimers. Our data suggest that COX-2 prostaglandins may be implicated in p53 function and p53 target gene expression.
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PMID:Prostaglandin E2 stimulates p53 transactivational activity through specific serine 15 phosphorylation in human synovial fibroblasts. Role in suppression of c/EBP/NF-kappaB-mediated MEKK1-induced MMP-1 expression. 1671 89

Epidemiological data suggest that epigallocatechin-3-gallate (EGCG) possesses chemopreventive properties against cancer. In this study, we examined the molecular mechanisms of EGCG in human pancreatic cancer cells. EGCG caused growth arrest at G1 stage of cell cycle through regulation of cyclin D1, cdk4, cdk6, p21/WAF1/CIP1 and p27/KIP1, and induced apoptosis through generation of reactive oxygen species and activation of caspase-3 and caspase-9. EGCG inhibited expressions of Bcl-2 and Bcl-XL and induced expressions of Bax, Bak, Bcl-XS and PUMA. Mouse embryonic fibroblasts (MEFs) derived from Bax and Bak double knockout mice exhibited greater protection against EGCG-induced apoptosis than wild-type or single knockout MEFs. EGCG caused Bax activation in p53 -/- MEFs, suggesting that EGCG can induce apoptosis in the absence of p53. Furthermore, the activities of Ras, Raf-1 and ERK1/2 were inhibited, whereas the activities of MEKK1, JNK1/2 and p38 MAP kinases were induced by EGCG. Inhibition of cRaf-1 or ERK enhanced EGCG-induced apoptosis, whereas inhibition of JNK or p38 MAP kinase inhibited EGCG-induced apoptosis. EGCG inhibited the activation of p90 ribosomal protein S6 kinase, and induced the activation of cJUN. Our results suggest that EGCG induces growth arrest and apoptosis through multiple mechanisms, and can be used for pancreatic cancer prevention.
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PMID:Epigallocatechin-3-gallate inhibits cell cycle and induces apoptosis in pancreatic cancer. 1756 28

Tumor progression locus-2 (Tpl-2) kinase is a member of the mitogen-activated protein kinase kinase kinase family that has been implicated in cellular transformation. The enhanced expression of this protein has been shown to activate both the mitogen-activated protein kinase and c-Jun N-terminal kinase pathways. However, the molecular mechanisms responsible for the oncogenic potential of Tpl-2 are still largely unknown. Here, we showed that Tpl-2 interacted with p53 both in vitro and ex vivo. The overexpression of Tpl-2 inhibited the epidermal growth factor (EGF)-induced p53 phosphorylation (Ser15) through upregulating the activity of protein phosphatase 2A, which interacted with p53 stimulated by EGF. Also, the EGF-induced p53 activity was suppressed in the Tpl-2 wild-type (WT)-transfected HEK 293 cells, but had no effect in the Tpl-2-mutant (S413A)-transfected cells. Furthermore, introduction of small interfering RNA-Tpl-2 into HEK 293 cells resulted in decreased cell viability compared with only adenovirus-p53-infected cells. In addition, the Tpl-2 WT, but not Tpl-2 mutant (S413A), showed increased EGF-induced c-fos promoter activity, followed by activator protein 1 (AP-1) transactivation activity, which was associated with the cell transformation prompted by the H-Ras-Tpl-2-AP-1 signaling axis. These results indicated that the Ser413 of Tpl-2 plays an important role in EGF-induced carcinogenesis as well as inactivation of the p53.
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PMID:Tpl-2 kinase downregulates the activity of p53 and enhances signaling pathways leading to activation of activator protein 1 induced by EGF. 1922 Oct 2

Despite our incomplete comprehension of how growth factor-stimulation of cells is linked to the cell cycle and of how the G(1)/S checkpoint is linked to initiation in DNA replication there is an unparalleled wealth of experimental evidence to connect protein phosphorylation to molecular mechanisms of carcinogenesis. Many growth factors, growth factor receptors with tyrosine kinase activity (insulin receptor, EGFR, PDGFR, CSF1R, NGFR, HGFR), nonreceptor serine/threonine or tyrosine kinases (c-Raf-1, cMos, c-Abl, c-Src) and cyclin D1 are encoded by oncogenes mutated or overexpressed in a variety of human tumors; the physiological functions of oncoproteins that are involved in gene expression and replication (c-Jun, T-antigen, c-Myc, c-Myb) as well as p53, RB and CDK4 tumor suppressor proteins and replication factor A are also regulated by phosphorylation, ms genes transduce growth factor receptor signals to protein kinase C (PKC) or to c-Raf-1 triggering two different cascades of protein kinases, the PKC and MAPK signaling pathways both targeting nuclear proteins. Thus cancer can be considered as a disease of the signaling pathways.
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PMID:The phosphorylation connection to cancer (review). 2155 34

Metformin may reduce the incidence of breast cancer and enhance response to neoadjuvant chemotherapy in diabetic women. This trial examined the effects of metformin on Ki67 and gene expression in primary breast cancer. Non-diabetic women with operable invasive breast cancer received pre-operative metformin. A pilot cohort of eight patients had core biopsy of the cancer at presentation, a week later (without treatment; internal control), then following metformin 500-mg o.d. for 1 week increased to 1-g b.d. for a further week continued to surgery. A further 47 patients had core biopsy at diagnosis were randomized to metformin (the same dose regimen) or no drug, and 2 weeks later had core biopsy at surgery. Ki67 immunohistochemistry, transcriptome analysis on formalin-fixed paraffin-embedded cores and serum insulin determination were performed blinded to treatment. Seven patients (7/32, 21.9%) receiving metformin withdrew because of gastrointestinal upset. The mean percentage of cells staining for Ki67 fell significantly following metformin treatment in both the pilot cohort (P = 0.041, paired t-test) and in the metformin arm (P = 0.027, Wilcoxon rank test) but was unchanged in the internal control or metformin control arms. Messenger RNA expression was significantly downregulated by metformin for PDE3B (phosphodiesterase 3B, cGMP-inhibited; a critical regulator of cAMP levels that affect activation of AMP-activated protein kinase, AMPK), confirmed by immunohistochemistry, SSR3, TP53 and CCDC14. By ingenuity pathway analysis, the tumour necrosis factor receptor 1 (TNFR1) signaling pathway was most affected by metformin: TGFB and MEKK were upregulated and cdc42 downregulated; mTOR and AMPK pathways were also affected. Gene set analysis additionally revealed that p53, BRCA1 and cell cycle pathways also had reduced expression following metformin. Mean serum insulin remained stable in patients receiving metformin but rose in control patients. This trial presents biomarker evidence for anti-proliferative effects of metformin in women with breast cancer and provides support for therapeutic trials of metformin.
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PMID:Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. 2165 90

p53 prevents cancer via cell cycle arrest, apoptosis, and the maintenance of genome stability. p53 also regulates energy-generating metabolic pathways such as oxidative phosphorylation (OXPHOS) and glycolysis via transcriptional regulation of SCO2 and TIGAR. SCO2, a cytochrome c oxidase assembly factor, is a metallochaperone which is involved in the biogenesis of cytochrome c oxidase subunit II. Here we have shown that SCO2 functions as an apoptotic protein in tumor xenografts, thus providing an alternative pathway for p53-mediated apoptosis. SCO2 increases the generation of reactive oxygen species (ROS) and induces dissociation of the protein complex between apoptosis signal-regulating kinase 1 (ASK-1) (mitogen-activated protein kinase kinase kinase [MAPKKK]) and its cellular inhibitor, the redox-active protein thioredoxin (Trx). Furthermore, SCO2 induces phosphorylation of ASK-1 at the Thr(845) residue, resulting in the activation of the ASK-1 kinase pathway. The phosphorylation of ASK-1 induces the activation of mitogen-activated protein kinase kinases 4 and 7 (MAP2K4/7) and MAP2K3/6, which switches the c-Jun N-terminal protein kinase (JNK)/p38-dependent apoptotic cascades in cancer cells. Exogenous addition of the SCO2 gene to hypoxic cancer cells and hypoxic tumors induces apoptosis and causes significant regression of tumor xenografts. We have thus discovered a novel apoptotic function of SCO2, which activates the ASK-1 kinase pathway in switching "on" an alternate mode of p53-mediated apoptosis. We propose that SCO2 might possess a novel tumor suppressor function via the ROS-ASK-1 kinase pathway and thus could be an important candidate for anticancer gene therapy.
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PMID:SCO2 induces p53-mediated apoptosis by Thr845 phosphorylation of ASK-1 and dissociation of the ASK-1-Trx complex. 2331 48


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