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)

In this study, we examined the cellular and molecular responses of fibroblasts cultured on a polyelectrolyte complex (PEC) derived from sulfated chitin as a polyanion and chitosan as a polycation. On PEC-coated dishes, the fibroblasts aggregated and then developed spheroid-like structures. At earlier stages of culture, DNA synthesis of cells cultured on PEC was stimulated approximately 75% higher than control cells. Among various signaling molecules examined, including mitogen-activated protein kinases, Akt/PKB and p53, an extracellular-signal-regulated kinase (ERK) was selectively and constitutively phosphorylated in cells cultured on PEC. The constitutive phosphorylation of ERK was derived from an activation of the ERK kinase MEK, but not from an inactivation of the ERK phosphatase MKP-1. Furthermore, ERK phosphorylation was almost abolished by a membrane receptor tyrosine kinase inhibitor. The enhanced phosphorylation of focal adhesion kinase, a downstream molecule of integrins, was also observed in cells cultured on PEC. These results suggest that fibroblasts recognize PEC as a continuous mitogenic stimulant which results in the constitutive activation of the MEK-ERK pathway toward mitogenesis. Further, PEC interacts with the cell membrane leading to activation of membrane molecules, including integrins and receptor tyrosine kinases. These responses may account, at least in part, for the potential use of PEC as a biomaterial for tissue regeneration.
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PMID:Enhanced DNA synthesis accompanied by constitutive phosphorylation of the ERK pathway in human fibroblasts cultured on a polyelectrolyte complex. 1453 74

Tuberous sclerosis (TSC) is a familial tumor syndrome due to mutations in TSC1 or TSC2, in which progression to malignancy is rare. Primary Tsc2(-/-) murine embryo fibroblast cultures display early senescence with overexpression of p21CIP1/WAF1 that is rescued by loss of TP53. Tsc2(-/-)TP53(-/-) cells, as well as tumors from Tsc2(+/-) mice, display an mTOR-activation signature with constitutive activation of S6K, which is reverted by treatment with rapamycin. Rapamycin also reverts a growth advantage of Tsc2(-/-)TP53(-/-) cells. Tsc1/Tsc2 does not bind directly to mTOR, however, nor does it directly influence mTOR kinase activity or cellular phosphatase activity. There is a marked reduction in Akt activation in Tsc2(-/-)TP53(-/-) and Tsc1(-/-) cells in response to serum and PDGF, along with a reduction in cell ruffling. PDGFRalpha and PDGFRbeta expression is markedly reduced in both the cell lines and Tsc mouse renal cystadenomas, and ectopic expression of PDGFRbeta in Tsc2-null cells restores Akt phosphorylation in response to serum, PDGF, EGF, and insulin. This activation of mTOR along with downregulation of PDGFR PI3K-Akt signaling in cells lacking Tsc1 or Tsc2 may explain why these genes are rarely involved in human cancer. This is in contrast to PTEN, which is a negative upstream regulator of this pathway.
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PMID:Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. 1456 7

Bisperoxovanadium (bpV) compounds are irreversible protein tyrosine phosphatase (PTP) inhibitors with a spectrum of activity distinct from that of vanadium salts. We studied the efficacy of a panel of bpVs as antineoplastic agents in vitro and in vivo with a view to investigating phosphatases as potential antineoplastic targets. The Cdc25A dual-specificity phosphatase is an oncoprotein required for progression through G(1)-S. It cooperates with oncogenic Ras to transform cells and is overexpressed in several cancers. Cdc25A is therefore an attractive candidate phosphatase target for the antineoplastic activity of bpV compounds. Cytotoxicity was examined in 28 cancer cell lines and in vivo efficacy was examined in a DA3 murine mammary carcinoma model. In vitro phosphatase assays were used to directly measure phosphatase inhibition, comparing Cdc25A to hVH2/DSP4, leukocyte antigen related/receptor type PTPF catalytic domain (LAR), Yersinia pestis phosphatase (YOPH), and T-cell PTPase/non-receptor type PTP2 (TCPTP). CDK2 activity and Rb phosphorylation were examined by immunocomplex kinase assays and Western blot. Cdc25A is at least 20-fold more sensitive to bpV inhibition than hVH2/DSP4, and 3- to 10- fold more sensitive than TCPTP and LAR. bpV inhibition of Cdc25A in cells leads to CDK2 inactivation and hypophosphorylation Rb, resulting in G1-S arrest and induction of p53-independent apoptosis. The most cytotoxic analogue, bpV[4,7-dimethyl-1,10-phenanthroline-bisperoxo-oxo-vanadium (Me2Phen)], shows submicromolar IC50s against a panel of cell lines and inhibited tumor growth by 80% in mice. These results demonstrate that bpVs may have significant antineoplastic activity. In addition, they are in vitro and in vivo inhibitors of phosphatases including Cdc25A, suggesting that phosphatases may be appropriate targets for novel antineoplastic agents and that further development of these agents, targeting them to specific phosphatases such as CDC25A, may lead to novel agents with enhanced antineoplastic activity.
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PMID:Cdc25A-inhibitory properties and antineoplastic activity of bisperoxovanadium analogues. 1457 70

Akt/protein kinase B is a serine/threonine kinase that plays a critical role in cell survival signaling, and its activation has been linked to tumorigenesis in several human cancers. Up-regulation of Akt, as well as its upstream regulator phosphatidylinositol 3-kinase, has been found in many tumors, and the negative regulator of this pathway, mutated in multiple advanced cancers suppressor (MMAC; also known as phosphatase and tensin homologue deleted on chromosome 10), is a tumor suppressor gene. We have investigated the effects of inhibiting Akt signaling in tumor cells by expression of an Akt kinase-dead mutant in which the two regulatory phosphorylation sites have been mutated to alanines. This mutant, which functions in a dominant negative manner (Akt-DN), was introduced into tumor cells using a replication-defective adenovirus expression system. As controls we used adenoviruses expressing p53, MMAC, beta-galactosidase, and empty virus. We show that in vitro proliferation of human and mouse tumor cells expressing high levels of activated/phosphorylated Akt was inhibited by both Akt-DN and p53, in comparison with control viruses expressing beta-galactosidase. Similarly, Akt-DN mutant expression led to selective induction of apoptosis in tumor cells expressing activated Akt. On the other hand, Akt-DN expression had minimal effect in normal and tumor cells expressing low levels of activated Akt. Expression of MMAC induced selective apoptosis in tumor cell lines in which MMAC is inactivated but not in tumor cells expressing wild-type levels of MMAC. In addition, the growth of tumor cells in a mouse model was also significantly inhibited by intratumoral injection of Akt-DN virus. These studies validate the usefulness of targeting Akt for new drug discovery efforts and suggest that inhibition of Akt may have a selective antitumor effect.
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PMID:Adenoviral-mediated expression of a kinase-dead mutant of Akt induces apoptosis selectively in tumor cells and suppresses tumor growth in mice. 1458 64

DNA damage activates the G2 cell cycle checkpoint to allow time for DNA repair before mitotic entry. The mechanism involves inhibition of the enzymatic activity for polo-like kinase 1 (Plk1), rendering Cdc25C with a basal phosphatase activity that is insufficient for converting Cdc2 to the fully active G2/M transition kinase. We found that cell cycle arrest at the G2/M boundary after ionizing radiation (IR) of breast carcinoma cells may involve repression of the gene for Plk1, PLK, mediated by the tumor-suppressor protein BRCA1. The p53-defective MT-1 cell line had an apparent accumulation of G2/M phase cells 12 h after irradiation. This response was preceded by a transient downregulation of PLK mRNA expression with a barely detectable level 6 h after exposure to IR but recovered after 12 h. A significantly lower fraction of irradiated BRCA1(-/-) HCC1937 cells arrested in the G2/M phase after 12 h, and the transient response of PLK mRNA was also considerably impaired. After reconstitution of wild-type BRCA1 in the HCC1937 cells however, downregulation of PLK mRNA as well as Plk1 protein expression after IR was restored. Moreover, the suppression of PLK mRNA expression 6 h after irradiation was completely abolished by the specific CHEK1 kinase inhibitor UCN-01, further indicating that the effector mechanism of DNA damage on PLK signals through BRCA1 and its downstream CHEK1. Our observations provide new information about the diversity of regulatory mechanisms governed by BRCA1 in DNA damage checkpoint control.
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PMID:Repression of mRNA for the PLK cell cycle gene after DNA damage requires BRCA1. 1465 92

The p53 tumor suppressor protein plays a critical role in mediating cellular response to stress. Upon DNA damage, post-translational modifications stabilize and activate this nuclear phosphoprotein. To determine the effect of phosphorylation site mutants in the context of the whole p53 protein, we performed reporter assays in p53 and MDM2 knockout mouse embryonic fibroblasts transfected with full-length p53 constructs. We show that mutation of S37 causes a decrease in p53 transcriptional activity compared to wild-type p53. Our data further suggest that the dephosphorylation of p53 at S37 is a regulated event involving protein phosphatase 2A (PP2A). Coimmunoprecipitation and immunofluorescence microscopy studies demonstrate that PP2A and p53 associate with one another in vivo following gamma-irradiation. Consistent with these observations, phosphorylated S37 accumulates in cell extracts prepared from gamma-irradiated Molt-4 cells in the presence of okadaic acid. Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37. These results suggest that dephosphorylation of p53 at S37 plays a role in the transcriptional regulation of the p53 protein in response to DNA damage.
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PMID:Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage. 1471 10

Genistein, a soy isoflavone, has a wide range of biological actions that suggest it may be of use in cancer prevention. We have recently reported that it arrests hepatoma cells at G2/M phase and inhibits Cdc2 kinase activity. In the present study, we examined the signaling pathway by which genistein modulates Cdc2 kinase activity in HepG2 cells and leads to G2/M arrest, and found that it caused an increase in both Cdc2 phosphorylation and expression of the Cdc2-active kinase, Wee1. Genistein also enhanced the expression of the cell cycle inhibitor, p21waf1/cip1, which interacts with Cdc2. Furthermore, phosphorylation/inactivation of Cdc25C phosphatase, which dephosphorylates/activates Cdc2, was increased. Genistein enhanced the activity of the checkpoint kinase, Chk2, which phosphorylates/inactivates Cdc25C, induced accumulation of p53, and activated the ataxia-telangiectasia-mutated (ATM) gene. Caffeine, an ATM kinase inhibitor, inhibited these effects of genistein on Chk2, p53, and p21waf1/cip1. These findings suggest that the effect of genistein on G2/M arrest in HepG2 cells is partly due to ATM-dependent Chk2 activation, an increase in Cdc2 phosphorylation/inactivation as a result of induction of Wee1 expression, and a decrease in Cdc2 activity as a result of induction of p21waf1/cip1 expression.
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PMID:Genistein arrests hepatoma cells at G2/M phase: involvement of ATM activation and upregulation of p21waf1/cip1 and Wee1. 1475 71

Targeting tumour suppressor gene pathways is an attractive therapeutic strategy in cancer. Since the first clinical trial took place in 1996, at least 20 other trials have investigated the possibility of restoring p53 function, either alone or in combination with chemotherapy, but with limited success. Other recent clinical trials have sought to harness abnormalities in the p53 pathway to permit tumour-selective replication of adenoviral vectors such as dl1520 (Onyx-015). Other tumour suppressor genes, such as retinoblastoma (Rb) and PTEN (phosphatase, tensin homologue, deleted on chromosome 10), are the targets for imminent clinical trials, while microarray technologies are revealing multiple new genes that are potential targets for future gene therapy.
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PMID:Gene therapy progress and prospects: cancer gene therapy using tumour suppressor genes. 1476 96

Modulation of tumor suppressor activities may provide new opportunities for cancer therapy. Here we show that disruption of the gene Ppm1d encoding Wip1 phosphatase activated the p53 and p16 (also called Ink4a)-p19 (also called ARF) pathways through p38 MAPK signaling and suppressed in vitro transformation of mouse embryo fibroblasts (MEFs) by oncogenes. Disruption of the gene Cdkn2a (encoding p16 and p19), but not of Trp53 (encoding p53), reconstituted cell transformation in Ppm1d-null MEFs. In vivo, deletion of Ppm1d in mice bearing mouse mammary tumor virus (MMTV) promoter-driven oncogenes Erbb2 (also called c-neu) or Hras1 impaired mammary carcinogenesis, whereas reduced expression of p16 and p19 by methylation-induced silencing or inactivation of p38 MAPK correlated with tumor appearance. We conclude that inactivation or depletion of the Wip1 phosphatase with resultant p38 MAPK activation suppresses tumor appearance by modulating the Cdkn2a tumor-suppressor locus.
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PMID:Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. 1505 81

The p53 tumor suppressor gene product plays an important role in the regulation of apoptosis. Transforming growth factor beta1 (TGF-beta1)-induced apoptosis in hepatic cells is associated with reduced expression of the retinoblastoma protein (pRb) and subsequent E2F-1-activated expression of apoptosis-related genes. In this study, we explored the potential role of p53 in TGF-beta1-induced apoptosis. HuH-7 human hepatoma cells were either synchronized in G1, S and G2/M phases, or treated with 1 nM TGF-beta1. The results indicated that greater than 90% of the TGF-beta1-treated cells were arrested in G1 phase of the cell cycle. This was associated with enhanced p53 dephosphorylation and p21(Cip1/Waf1) expression, which coincided with decreased Cdk2, Cdk4, and cyclin E expression, compared with synchronized G1 cells. In addition, p53 dephosphorylation coincided with caspase-3 activation, and translocation of p21(Cip1/Waf1) and p27(Kip1) into the cytoplasm, all of which were suppressed by caspase inhibition of TGF-beta1-induced apoptosis. Finally, phosphatase inhibition and pRb overexpression partially inhibited p53-mediated apoptosis. In conclusion, the results demonstrated that TGF-beta1-induced p53 dephosphorylation is associated with caspase-3 activation, and cytosolic translocation of p21(Cip1/Waf1) and p27(Kip1), resulting in decreased expression of Cdks and cyclins. Further, p53 appears to mediate TGF-beta1-induced apoptosis downstream of the pRb/E2F-1 pathway.
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PMID:p53 dephosphorylation and p21(Cip1/Waf1) translocation correlate with caspase-3 activation in TGF-beta1-induced apoptosis of HuH-7 cells. 1500 18


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