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)

LRP16 is a novel gene cloned from lymphocytic cells, and its function is not known. The expression level of LRP16 mRNA was up-regulated by estrogen in breast cancer MCF-7 cells based on the computed aided serial analysis of gene expression (SAGE) analysis. In this study, we investigate the effect of 17beta-estradiol (17beta-E(2)) on the expression of LRP16 mRNA and the effects of overexpression of LRP16 on the proliferation of cultured MCF-7 cells and the possible mechanisms involved. The expression level of LRP16 mRNA induced by 17beta-E(2) was determined by Northern blot analysis. LRP16 promoter-controlled luciferase expression vector (pGL3-S(0)) was co-transfected with various nuclear receptors, including estrogen receptor alpha and beta (ERalpha and ERbeta), glucocorticoid receptor alpha (GRalpha), androgen receptor (AR) and peroxisome-proliferator activated receptor gamma and alpha (PPARgamma and PPARgamma) into COS-7 cells, and the relative luciferase activity was measured using Dual-luciferase report assay systems. The effect of overexpression of LRP16 on MCF-7 proliferation was examined by the Trypan Blue exclusion method, and the cell cycle was analyzed by flow cytometry. The expression levels of cyclin E, p53 and p21(WAF1/CIP1) proteins were determined by Western blot analysis. The results showed (1) 17beta-E(2) induced a five- to eightfold increase in LRP16 mRNA levels in MCF-7 cells; (2) the relative luciferase activities in the COS-7 cells co-transfected by pGL3-S(0) and ERalpha or AR were 7.8-fold and 11-fold respectively of those in the control cells transfected by pGL3-S(0) alone; (3) overexpression of LRP16 stimulated MCF-7 cell proliferation, and the numbers of cells in the S-phase of the cell cycle in cells transfected with LRP16 increased about 10% compared with the control cells; and (4) cyclin E levels were much higher in cells with overexpression of LRP16 than in the control cells, while the expression levels of p53 and p21(WAF1/CIP1) were not different between the two groups of cells. From these results we concluded that estrogen up-regulates the expression level of LRP16 mRNA through activation of ERalpha and that overexpression of LRP16 promotes MCF-7 cell proliferation probably by increasing cyclin E.
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PMID:Up-regulation of LRP16 mRNA by 17beta-estradiol through activation of estrogen receptor alpha (ERalpha), but not ERbeta, and promotion of human breast cancer MCF-7 cell proliferation: a preliminary report. 1279 Jul 85

Vasopressin-activated Ca2+-mobilizing (VACM)-1 gene product is a 780-amino acid membrane protein that shares sequence homology with cullins, a family of genes involved in the regulation of cell cycle. However, when expressed in vitro, VACM-1 attenuates basal and vasopressin- and forskolin-induced cAMP production. Mutating the PKA-dependent phosphorylation site in the VACM-1 sequence (S730AVACM-1) prevents this inhibitory effect. To further examine the biological role of VACM-1, we studied the effect of VACM-1 and S730AVACM-1 proteins on cellular proliferation and gene expression in Chinese hamster ovary and COS-1 cells. Cellular proliferation of VACM-1-expressing cell lines was significantly lower compared with that of the vector-transfected cells, whereas it was significantly increased in S730AVACM-1-derived cell lines. Furthermore, expression of VACM-1 but not S730AVACM-1 protein retarded cytokinesis and prevented MAPK phosphorylation. Screening with the Human PathwayFinder-1 GEArray system and subsequent Western blot analysis demonstrated that VACM-1 induces p53 mRNA and protein expression. In summary, VACM-1 inhibits cellular growth by a mechanism that involves cAMP, MAPK phosphorylation, and p53 expression.
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PMID:VACM-1, a cul-5 gene, inhibits cellular growth by a mechanism that involves MAPK and p53 signaling pathways. 1291 6

Infection by high-risk HPV (human papillomavirus) is supposed to be the primary cause of cervical cancer. The HPV E2 protein (E2) is a DNA-binding protein that regulates viral gene expression and is required for efficient viral replication. Overexpression of the E2 protein in cervical cancer cells can induce growth arrest and/or apoptotic cell death, suggesting that E2 might be useful in the treatment of this disease. In the present study, we show that VP22 (herpes simplex virus VP22 protein) can be used to deliver E2 to target cells. VP22-E2 fusion proteins induce apoptosis in transiently transfected HPV-transformed cervical carcinoma cell lines. However, VP22-E2 fusion proteins do not kill COS-7 cells, probably because these cells constitutively express the simian-virus-40 T antigen and this protein sequesters the tumour suppressor protein p53. When COS-7 cells producing VP22-E2 are seeded into cultures of HPV-transformed cells, VP22-E2 enters the non-producing cells and induces apoptosis. VP22-E2 proteins produced in bacterial cells can also enter cervical cancer cells and induce apoptosis in a dose-dependent manner. Our results suggest that local delivery of VP22-E2 fusion proteins could be used to treat cervical cancer and other HPV-associated diseases.
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PMID:Herpes simplex virus VP22-human papillomavirus E2 fusion proteins produced in mammalian or bacterial cells enter mammalian cells and induce apoptotic cell death. 1470 62

F10, a subline of the B16 mouse melanoma cell line, is itself the parent of the more metastatic BL6 line. BL6 cells differ from F10 cells by an alteration of the gene encoding the B56gamma regulatory subunit of protein phosphatase 2A (PP2A), which results in mRNA encoding a truncated variant of the subunit (deltagamma1). Expression of deltagamma 1 protein is detectable only when BL6 cells are transplanted into mice and then gamma-irradiated. Recently, B56gamma subunit-containing PP2A holoenzymes have shown to dephosphorylate Mdm2, a negative regulator of p53. Thus, we assessed whether the expression of deltagamma1 affects irradiation-induced phosphorylation of Mdm2 and radioresistance of melanoma cells by perturbing the regulation of p53. Western blot analyses revealed that irradiated COS-7 and NIH3T3 cells stably expressing deltagamma1 showed significantly less irradiation-induced Mdm2 phosphorylation. Mdm2 phosphorylation reduces the ability of Mdm2 to target p53 for degradation, which probably explained why p53 protein levels in NIH3T3 cells expressing deltagamma1 were not significantly elevated by irradiation, unlike in wild-type cells. This was also true for F10 cells transfected with deltagamma1 (F10deltagamma1) when the cells expressed deltagamma1 after being irradiated in vivo. p53 mRNA levels in irradiated wild-type and deltagamma 1-expressing cells were both only slightly elevated, suggesting that Mdm2 regulates p53 levels by a post-transcriptional mechanism. p53-mediated induction of the pro-apoptotic gene encoding Bax was also significantly lower in F10deltagamma1 cells irradiated in vivo. Moreover, F10deltagamma1 and BL6 cells were less apoptotic than F10 cells when the cells were irradiated in vivo. The p53 in F10 cells appears to be as functional as that in NIH3T3 cells because irradiation-induced expression of p53-target genes was comparable in both cells. Collectively, deltagamma1 appears to reduce irradiation-induced Mdm2 phosphorylation, which then blocks irradiation-stimulated p53 accumulation. Defects, such as deltagamma1, in PP2A may thus contribute to melanoma cell radioresistance.
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PMID:A truncated isoform of the PP2A B56gamma regulatory subunit reduces irradiation-induced Mdm2 phosphorylation and could contribute to metastatic melanoma cell radioresistance. 1502

The tumor suppressor p53 is commonly inhibited under conditions in which the phosphatidylinositide 3'-OH kinase/protein kinase B (PKB)Akt pathway is activated. Intracellular levels of p53 are controlled by the E3 ubiquitin ligase Mdm2. Here we show that PKB inhibits Mdm2 self-ubiquitination via phosphorylation of Mdm2 on Ser(166) and Ser(188). Stimulation of human embryonic kidney 293 cells with insulin-like growth factor-1 increased Mdm2 phosphorylation on Ser(166) and Ser(188) in a phosphatidylinositide 3'-OH kinase-dependent manner, and the treatment of both human embryonic kidney 293 and COS-1 cells with phosphatidylinositide 3'-OH kinase inhibitor LY-294002 led to proteasome-mediated Mdm2 degradation. Introduction of a constitutively active form of PKB together with Mdm2 into cells induced phosphorylation of Mdm2 at Ser(166) and Ser(188) and stabilized Mdm2 protein. Moreover, mouse embryonic fibroblasts lacking PKBalpha displayed reduced Mdm2 protein levels with a concomitant increase of p53 and p21(Cip1), resulting in strongly elevated apoptosis after UV irradiation. In addition, activation of PKB correlated with Mdm2 phosphorylation and stability in a variety of human tumor cells. These findings suggest that PKB plays a critical role in controlling of the Mdm2.p53 signaling pathway by regulating Mdm2 stability.
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PMID:Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation. 1516 78

The open reading frame EP153R of African swine fever virus (ASFV) encodes a nonessential protein that has been involved in the hemadsorption process induced in virus-infected cells. By the use of a virus deletion mutant lacking the EP153R gene, we have detected, in several virus-sensitive cells, increased levels of caspase-3 and cell death as compared with those obtained after infection with the parental BA71V strain. Both transient and stable expression of the EP153R gene in Vero or COS cells resulted in a partial protection of the transfected lines from the apoptosis induced in response to virus infection or external stimuli. The presence of gene EP153R resulted in a reduction of the transactivating activity of the cellular protein p53 in Vero cell cultures in which apoptosis was induced by virus infection or staurosporine treatment. This is to our knowledge the first description of a viral C-type lectin with anti-apoptotic properties.
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PMID:The C-type lectin homologue gene (EP153R) of African swine fever virus inhibits apoptosis both in virus infection and in heterologous expression. 1526 4

In March 2003, a novel coronavirus was isolated from patients exhibiting atypical pneumonia, and was subsequently proven to be the causative agent of the disease now referred to as SARS (severe acute respiratory syndrome). The complete genome of the SARS-CoV (SARS coronavirus) has since been sequenced. The SARS-CoV nucleocapsid (SARS-CoV N) protein shares little homology with other members of the coronavirus family. In the present paper, we show that SARS-CoV N is capable of inducing apoptosis of COS-1 monkey kidney cells in the absence of growth factors by down-regulating ERK (extracellular-signal-regulated kinase), up-regulating JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) pathways, and affecting their downstream effectors. SARS-CoV N expression also down-regulated phospho-Akt and Bcl-2 levels, and activated caspases 3 and 7. However, apoptosis was independent of the p53 and Fas signalling pathways. Furthermore, activation of the p38 MAPK pathway was found to induce actin reorganization in cells devoid of growth factors. At the cytoskeletal level, SARS-CoV N down-regulated FAK (focal adhesion kinase) activity and also down-regulated fibronectin expression. This is the first report showing the ability of the N protein of SARS-CoV to induce apoptosis and actin reorganization in mammalian cells under stressed conditions.
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PMID:The SARS coronavirus nucleocapsid protein induces actin reorganization and apoptosis in COS-1 cells in the absence of growth factors. 1529 14

Human parvovirus B19 has been found in various tissues in addition to erythroid lineage cells, and non-structural protein (NS1) is reported to induce cytotoxicity and apoptosis in erythroid lineage cells, but the mechanism in non-permissive cells is still unclear. To address this issue, we have constructed the NS1 gene in a cytomegalovirus episomal vector, pEGFP-C1 and transfected it into monkey epithelial cells, COS-7. EGFP-NS1 expression in transfected cells was monitored and assessed by fluorescence microscopy, RT-PCR and Western blot. The flow cytometric analysis showed that the NS1-transfected cells were arrested at G1 phase by paclitaxel treatment and there was increased apoptosis. The expression of p53, an important molecule in apoptosis and cell cycle regulation, and its downstream cell cycle kinase inhibitors p16(INK4) and p21(WAF1/CIP1) were up-regulated in the NS1-transfected cells. Also, increased expression of the pro-apoptotic Bcl-2 members Bax, Bad and activation of caspase 3 and caspase 9, but not the activation of caspase 8 or Fas were detected in the NS1-transfected cells. p53-induced Bax expression and subsequent activation of caspase 9 is probably the apoptotic pathway in NS1-transfected cells since activation of the caspase 9 was suppressed by the p53 inhibitor and apoptosis was significantly inhibited by the caspase 9 inhibitor. Our results suggest that the cell death of the NS1-transfected cells is associated with mitochondria related apoptosis. These findings might provide alternative information for further study and characterization of B19 NS1 protein in B19 non-permissive cells.
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PMID:Human parvovirus B19 non-structural protein (NS1) induces apoptosis through mitochondria cell death pathway in COS-7 cells. 1537 Jun 68

A bispecific, single-chain antibody Fv fragment (Bs-scFv) was constructed from a single-chain Fv fragment of mAb 3E10 that penetrates living cells and localizes in the nucleus, and a single-chain Fv fragment of a non-penetrating antibody, mAb PAb421 that binds the C-terminal of p53. PAb421 binding restores wild-type functions of some p53 mutants, including those of SW480 human colon cancer cells. The Bs-scFv penetrated SW480 cells and was cytotoxic, suggesting an ability to restore activity to mutant p53. COS-7 cells (monkey kidney cells with wild-type p53) served as a control since they are unresponsive to PAb421 due to the presence of SV40 large T antigen that inhibits binding of PAb421 to p53. Bs-scFv penetrated COS-7 cells but was not cytotoxic, thereby eliminating non-specific toxicity of Bs-scFv unrelated to binding p53. A single mutation in CDR1 of PAb421 VH eliminated binding of the Bs-scFv to p53 and abrogated cytotoxicity for SW480 cells without altering cellular penetration, further supporting the requirement of PAb421 binding to p53 for cytotoxicity. Our study demonstrates the use of an antibody that penetrates living cells in the design of a bispecific single chain antibody to target and restore the function of an intracellular protein.
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PMID:Construction and expression of a bispecific single-chain antibody that penetrates mutant p53 colon cancer cells and binds p53. 1537 63

Klotho-mutated mice manifest multiple age-related disorders that are observed in humans. A recent study suggested that Klotho protein might function as an anti-aging hormone in mammals. Because it has been reported that apoptosis and senescence in vascular endothelial cells are closely related to the progression of atherosclerosis, we investigated Klotho's ability to interfere with apoptosis and cellular senescence in human umbilical vascular endothelial cells (HUVEC). Klotho overexpression decreased H(2)O(2)-induced apoptosis in COS-1 cells and Jurkat cells. Klotho protein also reduced H(2)O(2)- and etoposide-induced apoptosis in HUVEC. Caspase-3 and caspase-9 activity was lower in Klotho-treated HUVEC than in control cells. Senescence-associated beta-gal staining showed that Klotho protein interferes with H(2)O(2)-induced premature cellular senescence. The expression of p53 and p21 was lower in Klotho-treated cells. Our study suggests that Klotho acts as a humoral factor to reduce H(2)O(2)-induced apoptosis and cellular senescence in vascular cells.
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PMID:Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells. 1632 73


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