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)

The human protein DeltaNp53 and its murine counterpart p44 are isoforms of the tumor suppressor p53 lacking the transactivation domain present in the first 39 (40 in mouse) amino acids of the full-length protein. This makes them similar in structure to the DeltaN isoforms of the other members of the p53 superfamily of transcription factors, p63 and p73. The principle way both the human and the murine proteins are generated is by alternative translation of the p53 mRNA utilizing a start site in exon 4. Choice of start site depends on an interaction between p53 and its cognate RNA. When the balance between DeltaNp53 (p44) and full-length p53 is altered, the function of p53 as a transcription factor is disturbed. One consequence of over-expressing p44 in mice is an acceleration of the aging process and altered expression of genes in the IGF-1 signaling cascade [Maier, B., Gluba, W., Bernier, B., Turner, T., Mohammad, K., Guise, T., et al. (2004). Modulation of mammalian lifespan by the short isoform of p53. Genes & Development, 18, 306-319]. This links p53 to the single most important growth factor pathway known to regulate lifespan in lower organisms.
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PMID:DeltaNp53 or p44: priming the p53 pump. 1574 65

RARs (retinoic acid receptors) mediate the effect of their ligand RA (retinoic acid) on gene expression. We previously showed that RA inhibited cellular proliferation in part by decreasing expression of the mitogen activated protein kinase ERK1 (extracellular signal regulated kinase 1). However, the mechanism by which RA regulates ERK1 expression is largely uncharacterized. The present study characterizes coactivator-mediated regulation of RA target gene expression by analysing ERK1 promoter activation. CBP (CREB-binding protein) and PCAF (p300/CBP associated factor) are transcriptional coactivators that interact with nuclear hormone receptors such as RARs. CBP and PCAF differentially regulated ERK1 expression in stable clones. CBP clones expressed higher ERK1 protein levels, proliferated faster in culture and were resistant to RA-mediated growth inhibition. PCAF clones expressed lower levels of ERK1 protein and cells grew more slowly than controls. CBP and PCAF regulation of the ERK1 promoter was dependent on two Sp1 (specificity protein 1) sites located between -86 and -115 bp. Immunoprecipitation and yeast two-hybrid analysis revealed that PCAF interacted with Sp1 via CBP. A putative p53 binding site at -360 bp functioned as a major repressor of ERK1 promoter activity even in the absence of exogenous p53 expression. CBP and PCAF occupancy of the proximal ERK1 promoter was dramatically decreased by RA treatment. PCAF mediated inhibition of ERK1 expression was due to decreased stability of the kinase mRNA. We conclude that CBP and PCAF coactivators mediate ERK1 gene expression at both the transcriptional and post-transcriptional level.
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PMID:Regulation of ERK1 gene expression by coactivator proteins. 1605 Aug 10

To investigate the mechanism by which nitric oxide (NO) induces cell death in colon cancer cells, we compared two types of colon cancer cells with different p53 status: HCT116 (p53 wild-type) cells and SW620 (p53-deficient) cells. We found that S-nitrosoglutathione (GSNO), the NO donor, induced apoptosis in both types of colon cancer cells. However, SW620 cells were much more susceptible than HCT116 cells to apoptotic death by NO. We investigated the role of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 kinase on NO-induced apoptosis in both types of colon cancer cells. GSNO treatment effectively stimulated activation of the ERK1/2 and p38 kinase in both types of cells. In HCT116 cells, pretreatment with PD98059, an inhibitor of ERK1/2, or SB203580, an inhibitor of p38 kinase, had no marked effect on GSNO-induced apoptosis. However, in SW620 cells, SB203580 significantly reduced the NO-induced apoptosis, whereas PD098059 increases NO-induced apoptosis. Furthermore, we found evidence of cell cycle arrest of the G0/G1 phase in SW620 cells but not in HCT116 cells. Inhibition of ERK1/2 with PD098059, or of p38 kinase with SB203580, reduced the GSNO-induced cell cycle arrest of the G0/G1 phase in SW620 cells. We therefore conclude that NO-induced apoptosis in colon cancer cells is mediated by a p53-independent mechanism and that the pathways of ERK1/2 and p38 kinase are important in NO-induced apoptosis and in the cell cycle arrest of the G0/G1 phase.
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PMID:Association of the ERK1/2 and p38 kinase pathways with nitric oxide-induced apoptosis and cell cycle arrest in colon cancer cells. 1614 85

Glutamate antagonists limit the growth of human cancers in vitro. The mechanism of anticancer action of NMDA antagonists is not known, however. In this article, we report that the NMDA antagonist dizocilpine inhibits the extracellular signal-regulated kinase 1/2 pathway, an intracellular signaling cascade that is activated by growth factors and controls the proliferation of cancer cells. Dizocilpine reduces the phosphorylation of cAMP-responsive element binding protein, suppresses the expression of cyclin D1, up-regulates the cell cycle regulators and tumor suppressor proteins p21 and p53, and increases the number of lung adenocarcinoma cells in the G(2) and S phases of the cell cycle. Silencing of the tumor suppressor protein p21 abolishes antiproliferative action of dizocilpine. Consistent with inhibition of the extracellular signal-regulated kinase 1/2-signaling cascade, dizocilpine reverses the stimulation of proliferation induced by epidermal, insulin, and basic fibroblast growth factors in lung adenocarcinoma cells. Furthermore, dizocilpine prolongs the survival of mice with metastatic lung adenocarcinoma and slows the growth of neuroblastoma and rhabdomyosarcoma in mice. These findings reveal the mechanism of antiproliferative action of dizocilpine and indicate that it may be useful in the therapy of human cancers.
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PMID:NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth. 1623 Jun 11

In the present study, we have investigated the bee venom (BV) and melittin (a major component of BV)-mediated antiproliferative effect and defined its mechanisms of action in cultured rat aortic vascular smooth muscle cell(s) (VSMC). BV and melittin ( approximately 0.4-0.8 microg/ml) effectively inhibited 5% fetal bovine serum-induced and 50 ng/ml platelet-derived growth factor BB (PDGF-BB)-induced VSMC proliferation. The regulation of apoptosis has attracted much attention as a possible means of eliminating excessively proliferating VSMC. In the present study, the treatment of BV and melittin strongly induced apoptosis of VSMC. To investigate the antiproliferative mechanism of BV and melittin, we examined the effect of melittin on nuclear factor kappaB (NF-kappaB) activation, the PDGF-BB-induced IkappaBalpha phosphorylation, and its degradation were potently inhibited by melittin and whether DNA binding activity and nuclear translocation of NF-kappaB p50 subunit in response to the action of PDGF-BB were potently attenuated by melittin. In further investigations, melittin markedly inhibited the PDGF-BB-induced phosphorylation of Akt and weakly inhibited phosphorylation of extracellular signal-regulated kinase 1/2, upstream signals of NF-kappaB. Treatment of melittin also potently induced proapoptotic protein p53, Bax, and caspase-3 expression but decreased antiapoptotic protein Bcl-2 expression. These results suggest the antiproliferative effects of BV and melittin in VSMC through induction of apoptosis via suppressions of NF-kappaB and Akt activation and enhancement of apoptotic signaling pathway.
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PMID:Melittin inhibits vascular smooth muscle cell proliferation through induction of apoptosis via suppression of nuclear factor-kappaB and Akt activation and enhancement of apoptotic protein expression. 1640 28

Adenomyoepithelioma (AME) of the breast is an uncommon tumor characterized by biphasic proliferation of both epithelial and myoepithelial cells. In rare instances, the epithelial, the myoepithelial or both components of an AME may become malignant. Described herein is the case of a 69-year-old woman who presented with myoepithelial carcinoma of the breast in an AME. Malignancy of myoepithelial component (MEC) was evidenced by the presence of cytological atypia, high mitotic rate, necrosis and local invasion. Immunohistochemical study demonstrated strong expression of P53 and phosphorylated extracellular signal-regulated kinase 1/2 in MEC. Laser capture microdissection technique and mutational analysis further revealed point mutation of the p53 gene (T-->G transversion at codon 270) in this population, but not in glandular epithelial cells or adjacent normal ductal epithelium. No mutations in exons 1 and 2 of the K-, H-, and N-ras genes were identified in any of the neoplastic component. To the authors' knowledge this is the first report of a mutation in the p53 gene in a malignant AME of the breast.
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PMID:Myoepithelial carcinoma arising in an adenomyoepithelioma of the breast: case report with immunohistochemical and mutational analysis. 1663 67

Ochnaflavone (c-3 of apigenin-0-c-4 of apigenin; OC), a biflavonoid present in the human diet, is known to inhibit angiotensin II-induced hypertrophy and serum-induced smooth muscle cell proliferation. OC is known to have anti-fungal and anti-inflammatory activities. However, it is not known whether OC exerts similar cardioprotective effects in cells treated with tumor necrosis factor (TNF)-alpha. In this study, we isolated OC from Lonicera japonica and studied its effect on matrix metalloproteinase-9 (MMP-9) gene expression in human aortic smooth muscle cells (HASMC). Furthermore, we investigated whether OC exerts the multiple suppressive effects on cytokine TNF-alpha-induced HASMC. Treatment of OC showed its potent inhibitory effects on DNA synthesis of cultured HASMC in the presence of TNF-alpha. These inhibitory effects were associated with reduced extracellular signal-regulated kinase 1/2 (ERK1/2) activity and G1 cell cycle arrest. Treatment of OC, which induced a cell cycle block in G1-phase, induced downregulation of cyclins and CDKs and upregulation of the CDK inhibitor p21(waf1) expression, whereas upregulation of p27 or p53 by OC was not observed. Because anti-atherogenic effects need not be limited to anti-proliferation, we decided to examine whether OC exerts inhibitory effects on MMP-9 activity in TNF-alpha-induced HASMC. OC inhibited TNF-alpha-induced MMP-9 secretion on HASMC in a dose-dependent manner. This inhibition was characterized by downregulation of MMP-9, which was transcriptionally regulated at nuclear factor (NF)-kappaB site and activation protein (AP)-1 site in the MMP-9 promoter. These findings indicate the efficacy of OC in inhibiting cell proliferation, G1 to S-phase cell cycle progress, and MMP-9 expression through the transcription factors NF-kappaB and AP-1 on TNF-alpha-induced HASMC. The findings of the present study may provide a potential mechanism that explains the anti-atherogenic activity of OC.
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PMID:Ochnaflavone inhibits TNF-alpha-induced human VSMC proliferation via regulation of cell cycle, ERK1/2, and MMP-9. 1679 41

Connective tissue growth factor (CTGF) is a secreted protein that belongs to CCN family. The proteins in this family are implicated in various biological processes, such as angiogenesis, adhesion, migration, and apoptosis. In this study, we explored the roles of CTGF in lung tumorigenesis. The expression levels of CTGF in 58 lung cancer samples were reduced by >2 fold in 57% of the samples compared with matched normal samples using real-time reverse transcription-PCR. These results were confirmed by immunohistochemical staining for CTGF in normal lung epithelia and lung cancer. Cellular proliferation was inhibited in non-small cell lung cancer (NSCLC) cell lines NCI-H460, NCI-H520, NCI-H1299, and SK-MES-1 by CTGF overexpression. Partially purified CTGF suppressed lung cancer cell growth. The growth inhibition caused by CTGF overexpression was associated with growth arrest at G(0)-G(1) and prominent induction of p53 and ADP ribosylation factor. Most interestingly, overexpression of CTGF suppressed insulin-like growth factor-I-dependent Akt phosphorylation and epidermal growth factor-dependent extracellular signal-regulated kinase 1/2 phosphorylation. In summary, NSCLC cells expressed decreased levels of CTGF compared with normal lung cells; this lower expression has an effect on lung cancer cell proliferation and its cellular response to growth factors. Our data suggest that CTGF may behave as a secreted tumor suppressor protein in the normal lung, and its expression is suppressed in many NSCLCs.
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PMID:Suppression of cell proliferation and signaling transduction by connective tissue growth factor in non-small cell lung cancer cells. 1687 4

Cyclooxygenase-2 (COX-2) is antiapoptotic and is implicated in tumorigenesis. Recent reports, however, have also ascribed a proapoptotic action to inducible COX-2. We show here for the first time that a stilbene, resveratrol, induces nuclear accumulation of COX-2 protein in human breast cancer MCF-7 and MDA-MB-231 cell cultures. The induction of COX-2 accumulation by resveratrol is mitogen-activated protein kinase (MAPK; extracellular signal-regulated kinase 1/2)- and activator protein 1- dependent. Nuclear COX-2 in resveratrol-treated cells colocalizes with Ser(15)-phosphorylated p53 and with p300, a coactivator for p53-dependent gene expression. The interaction of COX-2, p53, and p300, as well as resveratrol-induced apoptosis, was inhibited by a MAPK activation inhibitor, PD98059. A specific inhibitor of COX-2, NS398, and small interfering RNA knockdown of COX-2 were associated with reduced p53 phosphorylation and consequent decrease in p53-dependent apoptosis in resveratrol-treated cells. We conclude that nuclear accumulation of COX-2 can be induced by resveratrol and that the COX has a novel intranuclear colocalization with Ser(15)-phosphorylated p53 and p300, which facilitates apoptosis in resveratrol-treated breast cancer cells.
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PMID:Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells. 1692 24

It has become clear that ultraviolet A (UVA) radiation from the solar spectrum is a major environmental challenge to the skin. This necessitates developing novel mechanism-based agents capable of ameliorating UVA-induced effects in the skin. We recently described a novel antioxidant, 3-O-Caffeoyl-1-methylquinic acid (MCGA3) from leaves of bamboo. Here, we investigated the photochemopreventive effects of MCGA3 against UVA-mediated apoptosis in immortalized HaCaT keratinocytes. Pretreatment of MCGA3 rendered cells more sensitive to subsequent UVA irradiation-induced apoptosis as well as completely reversed UVA-induced sustained phosphorylation of extracellular signal-regulated kinase 1/2 and protein kinase Calpha, downregulation of p21, and reactive oxygen species generation. Interestingly, MCGA3 itself effectively induced p21 protein and mRNA levels. Silencing of p21 by RNA interference revealed a pivotal role of p21 in generating G(1)-S arrest and in enhancing UVA-mediated apoptosis. Transcriptional activation of p21 by MCGA3 was mediated through the proximal region of multiple Sp1 sites regardless of p53-binding site in p21 promoter, and this effect was augmented by desferroioxamine, an iron chelating agent. Additional studies suggested that iron chelation-driven hypoxia by MCGA3 may function in activation of p21. MCGA3 could be a useful agent to prevent photocarcinogenesis via apoptotic elimination of p53 mutant and DNA-repair defective cells caused by UVA radiation.
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PMID:A novel antioxidant 3-O-Caffeoyl-1-methylquinic acid enhances ultraviolet A-mediated apoptosis in immortalized HaCaT keratinocytes via Sp1-dependent transcriptional activation of p21(WAF1/Cip1). 1714 35


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