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)

When growth is stimulated in the normally quiescent adult rat liver by partial hepatectomy, steady state levels of messenger RNAs (mRNAs) for c-fos, c-myc, and p53 increase sequentially during the prereplicative phase which precedes DNA synthesis. Levels of c-fos mRNA are elevated at least 4-fold within 15 min after partial hepatectomy and decrease rapidly by 2 h; c-myc mRNA reaches maximal levels (5-fold over normal) between 30 min and 2 h after the operation. A second, transient phase of expression for both c-fos and c-myc occurs around 8 h after partial hepatectomy. p53 mRNA levels increase between 8 and 12 h after the operation (5-fold over normal) and are reflected in an elevation of steady state levels of p53 protein between 12 and 15 h after partial hepatectomy. The levels of ras p21 protein increase much later at a time of active DNA replication and cell division. Actinomycin D injected at the time of partial hepatectomy blocks the increase in c-myc at 2 h but has no effect on c-fos mRNA levels. Actinomycin D injected at 6 h only partially blocks the increase in c-myc and p53 mRNA at 8 h but does not affect c-fos mRNA. Our results suggest that the transient and sequential expression of protooncogenes during the prereplicative stage of liver regeneration is likely to reflect events associated with entry and progression of hepatocytes into the cell cycle and can serve as markers for identifying specific humoral factors involved in liver regeneration.
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PMID:Sequential protooncogene expression during rat liver regeneration. 351 91

We investigated the sensitivity and sequential events that take place in thyroid epithelial cells after irradiation. Cell survival ratios at a dose of 2 Gy were 18 +/- 2.5%, 58 +/- 1.0%, 59 +/- 1.5%, and 98 +/- 1.8% in primary thyroid cells, papillary thyroid carcinoma cells, follicular thyroid carcinoma cells, and anaplastic thyroid carcinoma cells, respectively. Thyroid carcinoma cell lines carrying mutations in the p53 gene were resistant to ionizing radiation. Although irradiated cells were accumulated at G1 in primary thyroid cells even after low-dose irradiation (0.2 Gy), this phenomenon was not observed in the thyroid carcinoma cell lines. Wild-type p53 expression in primary thyroid cell was increased following irradiation, but mutated p53 in the thyroid carcinoma cell lines was unchanged. To clarify the signal transduction in the G1 arrest following irradiation, levels of expression of the p53 putative downstream effectors GADD45 and WAF1/Cip1 were examined. Despite the consistent level of GADD45 mRNA, the level of WAF1/Cip1 transcripts was increased in a radiation dose-dependent manner in primary thyroid cells. This increase in the WAF1/Cip1 mRNA level was observed 30 min after irradiation and continued for at least 48 h. A mobility shift assay performed using the sequence of the putative p53 DNA binding site on the WAF1/Cip1 and GADD45 genes as a probe showed that nuclear protein extracted from primary thyroid cells, anti-p53 antibody, and probe oligonucleotide-bound complex was clearly shifted. An increase in binding activity of the p53/antibody/DNA complex was observed following irradiation. In contrast, the nuclear extract from thyroid carcinoma cells could not bind the specific DNA site, suggesting that mutant p53 has lost its binding ability. Actinomycin D inhibited WAF1/Cip1 and GADD45 mRNA levels and cycloheximide stimulated up-regulation of both basal mRNA levels, but an additional increase of the mRNA expression following irradiation was observed only in the WAF1/Cip1 gene. These data suggest that p53 in postradiation acts at a transcriptional level on WAF1/Cip1 gene expression and that de novo protein synthesis is not required for this effect. These results suggest that the p53-WAF1/Cip1 pathway may play a central role in induction of G1 arrest following irradiation in human thyroid epithelial cells.
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PMID:Radiation-induced G1 arrest is selectively mediated by the p53-WAF1/Cip1 pathway in human thyroid cells. 774 5

The CDK-inhibitor p21WAF1/CIP1 has been implicated as a growth arrest mediator in p53-tumour suppression, cellular senescence and terminal differentiation. Cell type specific differences in p53-independent p21 expression and cell cycle arrest were found following treatment of human tumour cell lines with serum, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), or okadaic acid (OA). TPA induced p21 in ML1, K562 and HL60 leukemia cells, whereas OA induced p21 in SW480 and GM4723 carcinoma cells as well as in leukemic cells. In addition, TPA- and serum- but not OA-induced cell cycle arrest was reversed upon return of p21 to basal levels. To further investigate the mechanisms underlying p53-independent regulation of p21, the transcription inhibitor, Actinomycin D (AMD), was used to block p21 expression. The results showed a complete inhibition of p21 mRNA and protein induction by TPA or adriamycin but little effect on p21 mRNA induced by OA in the presence of AMD. These results suggested that TPA-induced p21 expression requires transcription initiation, while a post-transcriptional mechanism may be involved in OA-induction as well. Transient transfection assays with p21 promoter-luciferase reporters and TPA or OA treatment further confirmed that TPA, and to a lesser extent, OA, initiated transcription of p21. Finally, the protein kinase C inhibitor, staurosporine, was found to interfere with p21 induction and prevent cell cycle arrest following treatment with TPA but not OA, suggesting a requirement for PKC in TPA activation of p21 expression.
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PMID:Regulation of p21WAF1/CIP1 expression by p53-independent pathways. 862 72

We demonstrated that tumor necrosis factor-alpha (TNF-alpha) rapidly and markedly enhances p21 gene and protein expression prior to monocytic differentiation and apoptosis in p53-null HL-60 cells. TNF-alpha induced early small and delayed large peaks of apoptosis at 6 and 48 h of incubation, respectively. At 24 h of incubation, apparent monocytic differentiation of the cells was noted. Down-regulation of c-myc and c-myb and G0/G1 arrest were observed at 6-12 and 36 h, respectively. Actinomycin D markedly inhibited TNF-alpha-induced p21 mRNA expression, suggesting that the p21 gene is induced at the transcriptional level. We confirmed that TNF-alpha induces p53-independent apoptosis in HL-60 cells, which accompanies monocytic differentiation.
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PMID:p53-independent induction of p21 (WAF1/CIP1) during differentiation of HL-60 cells by tumor necrosis factor alpha. 899 Jun 24

The tumor suppressor p53 has been implicated in apoptosis induction and is mutated in human T-ALL CCRF-CEM cells. To investigate possible consequences of wild-type p53 loss, we reconstituted CEM-C7H2, a subclone of CCRF-CEM, with a temperature-sensitive p53 allele (p53ts). Stably transfected lines expressed high levels of p53ts and shift to the permissive temperature (32 degrees C) caused rapid induction of p53-regulated genes, such as p21(CIP1/WAF1), mdm-2 and bax. This was followed by extensive apoptosis within 24 h to 36 h, supporting the notion that mutational p53 inactivation contributed to the malignant phenotype. p53-dependent apoptosis was preceded by digestion of poly(ADP-ribose) polymerase, a typical target of interleukin-1beta-converting enzyme (ICE)-like proteases/caspases, and was markedly resistant to the ICE/caspase-1 and FLICE/caspase-8 inhibitor acetyl-Tyr-Val-Ala-Asp.chloromethylketone (YVAD), but sensitive to the CPP32/caspase-3 inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp.fluoromethylketone (DEVD) and benzyloxycarbonyl-Val-Ala-Asp.fluoromethylketone (zVAD), a caspase inhibitor with broader specificity. This indicated an essential involvement of caspases, but argued against a significant role of ICE/caspase-1 or FLICE/caspase-8. Actinomycin D or cycloheximide prevented cell death, suggesting that, in this system, p53-induced apoptosis depends upon macromolecule biosynthesis. Introduction of functional p53 into CEM cells enhanced their sensitivity to the DNA-damaging agent doxorubicin, but not to the tubulin-active compound vincristine. Thus, mutational p53 inactivation in ALL might entail relative resistance to DNA-damaging, but not to tubulin-destabilizing, chemotherapy.
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PMID:p53-induced apoptosis in the human T-ALL cell line CCRF-CEM. 939 39

Loss of normal p53 function was found frequently to interfere with response of cancer cells to conventional anticancer therapies. Since more than half of all human cancers possess p53 mutations, we decided to explore the involvement of mutant p53 in drug induced apoptosis. To further evaluate the relationship between the p53-dependent and p53-independent apoptotic pathways, and to elucidate the function of mutant p53 in modulating these processes, we investigated the role of a p53 temperature-sensitive (ts) mutant in a number of apoptotic pathways induced by chemotherapeutic drugs that are currently used in cancer therapy. To that end, we studied the M1/2, myeloid p53 non-producer cells, and M1/2-derived temperature-sensitive mutant p53 expressing clones. Apoptosis caused by DNA damage induced with gamma-irradiation, doxorubicin or cisplatin, was enhanced in cells expressing wild type p53 as compared to that seen in parental p53 non-producer cells; mutant p53 expressing clones were found to be more resistant to apoptosis induced by these factors. Actinomycin D, a potent inhibitor of transcription, as well as a DNA damaging agent, abrogated the restraint apoptosis mediated by mutant p53. These observations suggest that while loss of wild type p53 function clearly reduces the rate of apoptosis, p53 mutations may result in a gain of function which significantly interferes with chemotherapy induced apoptosis. Therefore, to achieve a successful cancer therapy, it is critical to consider the specific relationship between a given mutation in p53 and the chemotherapy selected.
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PMID:Mutant p53 protein expression interferes with p53-independent apoptotic pathways. 968 25

The TRAIL death receptor KILLER/DR5 is induced by DNA damaging agents in wild-type p53-expressing cells. Here we show that, unlike the p53-target CDK-inhibitor p21WAF1/CIP1, the TRAIL death receptor KILLER/DR5 is only induced in cells undergoing p53-dependent apoptosis and not cell cycle arrest. Thus GM glioblastoma cells carrying an inducible MMTV-driven p53 gene undergo cell cycle arrest and upregulate p21 but not KILLER/DR5 expression upon dexamethasone exposure. WI38 normal lung fibroblasts undergoing cell cycle arrest in response to ionizing irradiation also induce p21 but not KILLER/DR5 gene expression. KILLER/DR5 upregulation is also deficient in irradiated lymphoblastoid cells derived from patients with Ataxia Teleangiectasia suggesting a role for the ATM-p53 pathway in regulating KILLER/DR5 expression after DNA damage. Inhibition of transcription by Actinomycin D blocks both KILLER/DR5 and p21 induction in cells undergoing p53-dependent apoptosis. Our results suggest that the p53-dependent transcriptional induction of KILLER/DR5 death receptor is restricted to cells undergoing apoptosis and not cells undergoing exclusively p53-dependent G1 arrest.
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PMID:Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest. 1059 42

We have identified a novel p53 regulated gene designated DDA3 through differential mRNA display on IW32 erythroleukemia cells containing a temperature sensitive p53 allele, tsp53val-135. DDA3 mRNA induction could be observed in all sublines expressing tsp53val-135 cultured at permissive temperature as well as in NIH3T3 cells undergoing DNA damage. Upregulation of DDA3 could be detected within 2 h after down-shifting the temperature to 32.5 degrees C; upon shifting back to 38.5 degrees C, DDA3 mRNA rapidly degraded with a half-life of less than 2 h. Actinomycin D, but not cycloheximide, inhibited the p53 dependent DDA3 induction, suggesting that the activation is through transcriptional regulation and does not require de novo protein synthesis. DDA3 was expressed in multiple mouse tissues including brain, spleen, lung, kidney and testis. Full-length DDA3 cDNA was cloned and it contained an open reading frame predicted to encode a proline rich protein of 329 amino acids. Overexpression of DDA3 in H1299 lung carcinoma cells suppressed colony formation. These results suggest that DDA3 is a p53-regulated gene that might participate in the p53-mediated growth suppression.
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PMID:Identification of a novel mouse p53 target gene DDA3. 1061 17

Pancreatic cancer cells are usually resistant to apoptosis induced by cytotoxic drugs, by activation of surface receptors such as Fas and TNF receptor or by serum or growth factor withdrawal. Actinomycin D (actD) is an inhibitor of RNA synthesis and acts as a potent inducer of apoptosis in several cell lines. In the present study, we investigated the effects of actD on PANC-1 pancreatic cancer cells. ActD caused apoptosis in PANC-1 cells in a dose-dependent manner, as determined by cell growth assays, DNA laddering and TUNEL assays. Induction of apoptosis correlated with activation of the JNK/SAPK pathway and increased expression of Bax but not Bad or p53. PANC-1 cells were completely resistant to Fas antibody and TNF-alpha. In contrast, TRAIL decreased the growth of PANC-1 cells by 22%. Low concentrations of actD (10 ng/ml) enhanced the cytotoxic effects of all 3 cytokines. EGF, FGF-2 and IGF-I did not protect PANC-1 cells from actD-mediated apoptosis. ActD (10 ng/ml) also inhibited the growth of CAPAN-1 and T3M4 pancreatic cancer cells but not MiaPaCa-2 cells. Our observations suggest that actD may act via JNK/SAPK and Bax to promote apoptosis in PANC-1 cells and that it may inhibit the growth of other pancreatic cancer cell lines.
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PMID:Actinomycin D induces apoptosis and inhibits growth of pancreatic cancer cells. 1076 Aug 29

A novel method was developed to determine the oxidation status of proteins in cultured cells. Methoxy-polyethylene glycol-maleimide MW 2000 (MAL-PEG) was used to covalently tag p53 protein that was oxidized at cysteine residues in cultured cells. Treatment of MCF7 breast cancer cells with pyrrolidine dithiocarbamate (PDTC), a metal chelator, resulted in a minimum of 25% oxidation of p53. The oxidized p53 had an average of one cysteine residue oxidized per p53 protein molecule. The effect of PDTC treatment on downstream components of the p53 signal-transduction pathway was tested. PDTC treatment prevented actinomycin D-mediated up-regulation of two p53 effector gene products, murine double minute clone 2 oncoprotein and p21(WAF1/CIP1) (where WAF1 corresponds to wild-type p53-activated fragment 1 and CIP1 corresponds to cyclin-dependent kinase-interacting protein 1). Actinomycin D treatment led to accumulation of p53 protein in the nucleus. However, when cells were simultaneously treated with PDTC and actinomycin D, p53 accumulated in both the nucleus and the cytoplasm. The data indicate that an average of one cysteine residue per p53 protein molecule is highly sensitive to oxidation and that p53 can be efficiently oxidized by PDTC in cultured cells. PDTC-mediated oxidation of p53 correlates with altered p53 subcellular localization and reduced activation of p53 downstream effector genes. The novel method for detecting protein oxidation detailed in the present study may be used to determine the oxidation status of specific proteins in cells.
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PMID:p53 protein oxidation in cultured cells in response to pyrrolidine dithiocarbamate: a novel method for relating the amount of p53 oxidation in vivo to the regulation of p53-responsive genes. 1099 50


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