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)

Our aim was to study the anticancer effect of the novel immunomodulator FTY720 in vitro and in vivo by investigation of cell cycle entry, cell cycle regulation, cell survival and apoptosis pathways. Three hepatoma cell lines with different p53 statuses (HepG2, Huh-7 and Hep3B) and one non-tumorigenic immortalized liver cell line (MIHA) were used for an in vitro study. The in vivo effects of FTY720 were evaluated in a nude mouse tumor model. Cell cycle distribution and cell cycle regulator proteins p27(Kip1) and cyclin D1, together with the PI3-K/Akt pathway, mitogen-activated protein kinases and cleaved caspase-3 and caspase-9, were evaluated. FTY720 selectively induced cell apoptosis in hepatoma cell lines with overexpression of cleaved caspase-3 and caspase-9, but the same phenomena were not found in MIHA cells. FTY720 induced Akt dephosphorylation at Ser473 mediated by phosphoinositide 3-kinase (PI3-K) inhibition. Dephosphorylation led to down-regulation of p42/p44 and dephosphorylation of Forkhead transcription factor and GSK-3beta and, subsequently, up-regulation of p27(Kip1) and down-regulation of cyclin D1. In our in vivo model FTY720 induced apoptosis of tumor cells by down-regulation of the Akt pathway. FTY720 suppressed tumor growth without notable side-effects in normal liver. In conclusion, FTY720 is a novel anticancer agent that induces apoptosis of hepatoma cell lines both in vitro and in vivo through PI3-K-mediated Akt dephosphorylation in a p53-independent manner.
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PMID:FTY720 induces apoptosis of human hepatoma cell lines through PI3-K-mediated Akt dephosphorylation. 1529 71

Phosphorylation at multiple sites within the N-terminus of p53 promotes its dissociation from hdm2/mdm2 and stimulates its transcriptional regulatory potential. The large phosphoinositide 3-kinase-like kinases ataxia telangiectasia mutated gene product and the ataxia telangectasia and RAD-3-related kinase promote phosphorylation of human p53 at Ser15 and Ser20, and are required for the activation of p53 following DNA damage. DNA-dependent protein kinase (DNA-PK) is another large phosphoinositide 3-kinase-like kinase with the potential to phosphorylate p53 at Ser15, and has been proposed to enhance phosphorylation of these sites in vivo. Moreover, recent studies support a role for DNA-PK in the regulation of p53-mediated apoptosis. We have shown previously that colocalization of p53 and DNA-PK to structured single-stranded DNA dramatically enhances the potential for p53 phosphorylation by DNA-PK. We report here the identification of p53 phosphorylation at two novel sites for DNA-PK, Thr18 and Ser9. Colocalization of p53 and DNA-PK on structured DNA was required for efficient phosphorylation of p53 at multiple sites, while specific recognition of Ser9 and Thr18 appeared to be dependent upon additional determinants of p53 beyond the N-terminal 65 amino acids. Our results suggest a role for DNA-PK in the modulation of p53 activity resultant from the convergence of p53 and DNA-PK on structured DNA.
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PMID:Structured DNA promotes phosphorylation of p53 by DNA-dependent protein kinase at serine 9 and threonine 18. 1535 54

The phosphoinositide 3-kinase (PI3-kinase) signalling pathway plays a key role in the regulation of cell survival and proliferation. We show that the PI3-kinase/Akt pathway is constitutively active in primary acute myeloid leukaemia (AML) cells and that blockade by the selective inhibitor LY294002 reduces survival of the total blast population (mean 52%). The ERK/MAPK module is also constitutively active and treatment with the MAPKK inhibitor U0126 reduces cell survival by 22%. In 10 of 18 samples, PI3-kinase contributes to MAPK activation as incubation with LY294002 leads to a marked reduction in its phosphorylation. PI3-kinase inhibition reduces survival of the CD34+38- AML progenitor subset by 44%, whereas MAPKK inhibition has little effect. Reporter assays in primary AML cells show that blocking PI3-kinase leads to a marked reduction of constitutive NF-kappaB activity and promotes p53-mediated transcription. This is associated with a synergistic interaction between LY294002 and Ara-C. An inducible activated form of Akt protects normal myeloid cells from Ara-C and etoposide-mediated apoptosis. These results show that blocking PI3-kinase has direct antileukaemic effects and potentiates the response to conventional cytotoxics via a number of targets including NF-kappaB, p53 and MAPK. Inhibitors of PI3-kinase and Akt may be useful in the treatment of AML.
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PMID:PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways. 1570 83

We previously demonstrated that the nitroxide antioxidant tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) increased latency to tumorigenesis and doubled (100%) the lifespan of Atm-deficient mice, a mouse model of ataxia telangiectasia, which displays accelerated oxidative damage and stress. Tempol treatment of cancer-prone p53-deficient mice resulted in a small but significant (25%) increase in lifespan by prolonging latency to tumorigenesis, demonstrating that existing oxidative stress and damage are not necessary for the chemopreventative effects of tempol. However, the relatively small effect on latency in p53-deficient mice and the finding that tempol-mediated resistance to oxidative insult was p53-dependent suggested a more direct role of p53 in the chemopreventative effects of tempol. Surprisingly, tempol treatment specifically increased serine 18 phosphorylation of p53 (but not gamma-H2AX) and p21 expression in primary thymocytes in vitro in a p53-dependent fashion. Inhibition of phosphoinositide 3-kinase (PI3K) family members suggested that SMG-1 was responsible for the tempol-mediated enhancement of p53 serine 18 phosphorylation. These data suggest that the chemopreventative effect of tempol is not solely due to the reduction of oxidative stress and damage but may also be related to redox-mediated signaling functions that include p53 pathway activation.
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PMID:Cancer chemoprevention by the antioxidant tempol acts partially via the p53 tumor suppressor. 1588 86

Multiple genetic alterations occur in melanoma, a lethal skin malignancy of increasing incidence. These include mutations that activate Ras and two of its effector cascades, Raf and phosphoinositide 3-kinase (PI3K). Induction of Ras and Raf can be caused by active N-Ras and B-Raf mutants as well as by gene amplification. Activation of PI3K pathway components occurs by PTEN loss and by AKT3 amplification. Melanomas also commonly show impairment of the p16(INK4A)-CDK4-Rb and ARF-HDM2-p53 tumor suppressor pathways. CDKN2A mutations can produce p16(INK4A) and ARF protein loss. Rb bypass can also occur through activating CDK4 mutations as well as by CDK4 amplification. In addition to ARF deletion, p53 pathway disruption can result from dominant negative TP53 mutations. TERT amplification also occurs in melanoma. The extent to which these mutations can induce human melanocytic neoplasia is unknown. Here we characterize pathways sufficient to generate human melanocytic neoplasia and show that genetically altered human tissue facilitates functional analysis of mutations observed in human tumors.
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PMID:Use of human tissue to assess the oncogenic activity of melanoma-associated mutations. 1595 21

The role of insulin-like growth factor (IGF-1) as neural survival factor for the treatment of Alzheimer's disease has recently gained attention. The present study shows that IGF-1 protects lymphocytes from (10, 30 microM) Abeta[(25-35)] and (25, 50, 100 microM) H(2)O(2)-induced apoptosis through NF-kappaB activation and p53 down regulation involving the phosphoinositide 3-kinase (PI-3K)-dependent pathway as demonstrated by using either (25 microM) LY294002 (PI-3K inhibitor), (10 nM) ammonium pyrrolidinedithiocarbamate (PDTC; NF-kappaB inhibitor), 50 nM pifithrin-alpha (PFT; p53 inhibitor) or by using immunocytochemistry detection of NF-kappaB and p53 transcription factors activation. Importantly, IGF-1, PDTC and PFT were able to protect and rescue lymphocytes pre-exposed to 10 muM Abeta[(25-35)], even when the three compounds were added up-to 12 h post- Abeta[(25-35)] exposure. Altogether these results suggest that survival/rescue of lymphocytes from Abeta[(25-35)] toxicity is determined by p53 inactivation via IGF-1/ PI-3K pathway.
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PMID:Insulin-like growth factor-1 prevents Abeta[25-35]/(H2O2)- induced apoptosis in lymphocytes by reciprocal NF-kappaB activation and p53 inhibition via PI3K-dependent pathway. 1639 95

We determined one mechanism by which the putative phosphoinositide-dependent kinase (PDK)-1 inhibitor 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}acetamide (OSU-03012) killed primary human glioma and other transformed cells. OSU-03012 caused a dose-dependent induction of cell death that was not altered by p53 mutation, expression of ERBB1 vIII, or loss of phosphatase and tensin homolog deleted on chromosome 10 function. OSU-03012 promoted cell killing to a greater extent in glioma cells than in nontransformed astrocytes. OSU-03012 and ionizing radiation caused an additive, caspase-independent elevation in cell killing in 96-h viability assays and true radiosensitization in colony formation assays. In a cell type-specific manner, combined exposure to OSU-03012 with a mitogen-activated protein kinase kinase 1/2 inhibitor, phosphoinositide 3-kinase/AKT inhibitors, or parallel molecular interventions resulted in a greater than additive induction of cell killing that was independent of AKT activity and caspase function. OSU-03012 lethality as a single agent or when combined with signaling modulators was not modified in cells lacking expression of BIM or of BAX/BAK. OSU-03012 promoted the release of cathepsin B from the lysosomal compartment and release of AIF from mitochondria. Loss of BH3-interacting domain (BID) function, overexpression of BCL(XL), and inhibition of cathepsin B function suppressed cell killing and apoptosis-inducing factor (AIF) release from mitochondria. In protein kinase R-like endoplasmic reticulum kinase-/- cells, the lethality of OSU-03012 was attenuated which correlated with reduced cleavage of BID and with suppression of cathepsin B and AIF release into the cytosol. Our data demonstrate that OSU-03012 promotes glioma cell killing that is dependent on endoplasmic reticulum stress, lysosomal dysfunction, and BID-dependent release of AIF from mitochondria, and whose lethality is enhanced by irradiation or by inhibition of protective signaling pathways.
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PMID:OSU-03012 promotes caspase-independent but PERK-, cathepsin B-, BID-, and AIF-dependent killing of transformed cells. 1662 74

Y-box binding proteins, belonging to a family of multifunctional proteins conserved from bacteria to human, are involved in transcriptional and translational regulation of various genes, mRNA alternative splicing, DNA replication and repair, as well as cell proliferation. A typical Y-box binding protein contains three structure domains, namely the N-terminal domain, the hydrophilic C-terminal domain and the conserved cold shock domain (CSD) which binds strongly to inverted CCAAT box found in different promoters and determines protein function.Y-box binding proteins may play an important physiological role in cell proliferation.For example, the human Y-box protein 1 (YB-1) may be repressed in the oncogenic phosphoinositide 3-kinase (PI3K) pathway. In addition, it may also act as a negative regulator of p53. It has been demonstrated that YB-1 represses transcription of the p53 promoter in a sequence-specific manner using specifically reporter assays. This implies that YB-1 may, in some situations, protect cells from p53-mediated apoptosis, indicating that YB-1 may be a good target for the development of a new therapeutics.The function of Y-box binding protein and its effect on carcinogenesis are summarized in the paper. We hope to further explore the functional roles of Y-box binding protein, and provide some helpful lines and suggestions for tumor control.
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PMID:[Functions of Y-box binding protein and its role in tumorigenicity]. 1696 28

Cannabinoids have been suggested as potential neuroprotective compounds in Alzheimer's disease (AD). Despite intense investigation, the detailed intracellular mechanism(s) involved in cannabinoids survival effect remains to be elucidated. The present study shows that CP55,940 (a CB1 and CB2 agonist) and JWH-015 (a CB2 agonist) protect and rescue peripheral blood lymphocytes (PBL) from (10 microM) Abeta[(25-35)] and (50 microM) H(2)O(2)-induced apoptosis by two alternative mechanisms: (1) receptor-independent pathway, as demonstrated by no-dihydrorhodamine oxidation into fluorescent rhodamine 123 (R-123) as a result of cannabinoid inhibition of Abeta-generated H(2)O(2); (2) receptor-dependent pathway through NF-kappaB activation and p53 down regulation involving phosphoinositide 3-kinase (PI-3K), as demonstrated by using either (25 microM) LY294002 (a PI-3K inhibitor), (50 nM) pifithrin-alpha (PFT, a specific p53 inhibitor) or by using immunocytochemistry detection of NF-kappaB and p53 transcription factors activation. Importantly, cannabinoid agonists and PFT were able to protect and rescue lymphocytes pre-exposed to toxicants-, even when the three compounds were added up-to 12 h post-Abeta[(25-35)]/(H(2)O(2)) exposure. These results suggest that CP55,940/( JWH-015) protection/rescue of PBL from noxious stimuli is determined by p53 inactivation. These findings may contribute to a better understanding of the role played by cannabinoids as neuroprotective agents to target and interrupt molecular signaling that induce damage in AD disorder.
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PMID:Avoidance of Abeta[(25-35)] / (H(2)O(2)) -induced apoptosis in lymphocytes by the cannabinoid agonists CP55,940 and JWH-015 via receptor-independent and PI3K-dependent mechanisms: role of NF-kappaB and p53. 1701 86

Despite the understanding of the importance of phosphoinositide 3-kinase (PI 3-K) signaling pathway in the regulation of cellular proliferation, little is known about its role during phorbol 12-myristate 13-acetate (PMA)-induced differentiation in human leukemia cells. Here, we report a novel finding that PI 3-K inhibition by LY294002 significantly increases p21WAF1/Cip1 expression in PMA-stimulated human leukemia cells NB4 and THP1. LY294002 potentiated expression of p21WAF1/Cip1 via a p53-independent mechanism and did not affect mitogen activated protein kinase (MAPK) activation. Electrophoretic mobility shift (EMSA) experiments revealed that blocking of PI 3-K was associated with increased binding of transcription factor Sp1 to the PMA-responsive sites on the p21WAF1/Cip1 promoter. Pretreatment with rapamycin, an inhibitor of mTOR kinase, decreased the expression of p21WAF1/Cip1 protein in PMA-stimulated NB4 cells. The level of PMA-induced p21WAF1/Cip1 protein expression was lower in NB4 cells overexpressing wild type protein kinase C zeta (PKC zeta) compared to those transfected with empty vector or with kinase inactive PKC zeta. Sp1 binding to the p21WAF1/Cip1 promoter was completely lost in a wild type PKC zeta overexpressing and PMA-stimulated NB4 cells. We demonstrate that PI 3-K signaling pathway suppresses PMA-induced expression of p21WAF1/Cip1 in human leukemia cells, and that this effect is partly mediated by PKC zeta.
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PMID:PI 3-K signaling pathway suppresses PMA-induced expression of p21WAF1/Cip1 in human leukemia cells. 1728 1


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