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)

Incubating human cells in diethylmaleate (DEM) depletes the intracellular pool of reduced glutathione (GSH) and increases the concentration of oxidative free radicals. We found that DEM-induced oxidative stress reduced the ability of p53 to bind its consensus recognition sequence and to activate transcription of a p53-specific reporter gene. Nevertheless, DEM treatment induced expression of WAF1/CIP1 but not GADD45 mRNA. The fact that N-acetylcysteine, a precursor of GSH that blocks oxidative stress, prevented WAF1/CIP1 induction by DEM suggests that WAF1/CIP1 induction probably was a consequence of the ability of DEM to reduce intracellular GSH levels. DEM induced WAF1/CIP1 expression in Saos-2 and T98G cells, both of which lack functional p53 protein. DEM treatment did not produce an increase in membrane-associated protein kinase C, but ERK2, a mitogen-activated protein kinase, was phosphorylated in a manner consistent with ERK2 activation. DEM treatment also produced a dose-dependent delay in cell cycle progression, which at low concentrations (0.25 mM) consisted of a G2/M arrest and at higher concentrations (1 mM) also involved G1 and S phase delays. Our results indicate that oxidative stress induces WAF1/CIP1 expression and arrests cell cycle progression through a mechanism that is independent of p53. This mechanism may provide for cell cycle checkpoint control under conditions that inactivate p53.
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PMID:A p53-independent pathway for activation of WAF1/CIP1 expression following oxidative stress. 749 74

UVB irradiation inhibits melanocyte proliferation by causing arrest in G1 (D. Barker, K. Dixon, E. E. Medrano, D. Smalara, S. Im, D. Mitchell, G. Babcock, and Z. A. Abdel-Malek. Cancer Res., 55: 4041-4046, 1995). To determine how, after UVB irradiation, signal transduction pathways, DNA damage, and cell cycle arrest interact in the human melanocyte, we analyzed here the possible activation of tyrosine kinases, the serine-threonine kinases Baf-1 and ERK2, the status of the transcription factor c-fos, and the activation of cell cycle checkpoints induced by expression of p53 protein. We found that in contrast to the UVC response, exposure to UVB irradiation did not stimulate the above kinases. UVB light induced a prolonged c-fos expression, suggesting a mechanism of induction different from the transient expression elicited by growth factors. The tumor suppressor p53 and the p53-inducible cyclin-dependent kinase inhibitor protein p21Waf-1/SDI-1/Cip-1 were expressed at high levels for at least 2 days after UV-irradiation. In parallel, phosphorylation of Rb, the retinoblastoma tumor suppressor gene product, was halted in UVB-irradiated cells and correlated with the expression of the protein p21Waf-1/SDI-1/Cip-1. Our data define for the first time how UVB irradiation affects the expression of crucial regulatory events needed for cell cycle progression in the human melanocyte.
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PMID:Ultraviolet B light induces G1 arrest in human melanocytes by prolonged inhibition of retinoblastoma protein phosphorylation associated with long-term expression of the p21Waf-1/SDI-1/Cip-1 protein. 766 78

The organochlorine pesticide heptachlor constitutes a potential health hazard because of its persistence in nature, its reported contamination in food and milk, and its possible carcinogenic effects. As a tumor promoter, heptachlor induces human myeloblastic leukemia cells to differentiate, and also down-regulates the tumor suppressor gene p53 in human immune cells. In this study, the heptachlor signaling pathway in human lymphocytes was studied. Addition of heptachlor to human CEM x174 lymphocytic cells reduced the cellular levels of MAP kinase (MAPK, mitogen-activated protein kinase) cascade proteins, including ERK1 (a 44-kDa MAPK), ERK2 (a 42-kDa MAPK), a 85-kDa and a 54-kDa MAP kinase, MEK1 (a 45-kDa ERK kinase) and MEKK (a 78-kDa MEK kinase). However, heptachlor treatment caused a marked increase in the expression of the activated (Thr- and Tyr-dually phosphorylated) ERK1 and ERK2 in the cells. These studies indicate that mitogen-activated protein kinases are important intermediates in the signal transduction pathway of immune cells upon heptachlor exposure, and the observation of stimulation of activated MAP kinases without a simultaneous accumulation of basal enzymes may suggest the involvement of a negative feedback control mechanism in the pathway.
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PMID:Heptachlor and the mitogen-activated protein kinase module in human lymphocytes. 970 2

The polyamines spermidine and spermine and their precursor putrescine are intimately involved in and are required for cell growth and proliferation. This study examines the mechanism by which polyamines modulate cell growth, cell cycle progression, and signal transduction cascades. IEC-6 cells were grown in the presence or absence of DL-alpha-difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase, which is the first rate-limiting enzyme for polyamine synthesis. Depletion of polyamines inhibited growth and arrested cells in the G1 phase of the cell cycle. Cell cycle arrest was accompanied by an increase in the level of p53 protein and other cell cycle inhibitors, including p21(Waf1/Cip1) and p27(Kip1). Induction of cell cycle inhibitors and p53 did not induce apoptosis in IEC-6 cells, unlike many other cell lines. Although polyamine depletion decreased the expression of extracellular signal-regulated kinase (ERK)-2 protein, a sustained increase in ERK-2 isoform activity was observed. The ERK-1 protein level did not change, but ERK-1 activity was increased in polyamine-depleted cells. In addition, polyamine depletion induced the stress-activated protein kinase/c-Jun NH2-terminal kinase (JNK) type of mitogen-activated protein kinase (MAPK). Activation of JNK-1 was the earliest event; within 5 h after DFMO treatment, JNK activity was increased by 150%. The above results indicate that polyamine depletion causes cell cycle arrest and upregulates cell cycle inhibitors and suggest that MAPK and JNK may be involved in the regulation of the activity of these molecules.
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PMID:Polyamine depletion arrests cell cycle and induces inhibitors p21(Waf1/Cip1), p27(Kip1), and p53 in IEC-6 cells. 1006 96

The p53 tumor suppressor protein is a transcription factor that plays a key role in the process of apoptosis and the cell's defense against tumor development. Activation of p53 occurs, at least in part, by phosphorylation of its protein. Very recently it has been reported that UV induced a functional activation of p53 via phosphorylation at serine 389. Here, we report that the UV-induced phosphorylation of p53 at serine 389 is mediated by p38 kinase. UVC-induced phosphorylation of p53 at serine 389 was markedly impaired by either pretreatment of cells with p38 kinase inhibitor, SB202190, or stable expression of a dominant negative mutant of p38 kinase. In contrast, there was no inhibition observed in cells treated with specific MEK1 inhibitor, PD98059, or with stable expression of a dominant negative mutant of ERK2 or JNK1. Most importantly, p38 kinase could be co-immunoprecipitated with p53 by using antibodies against p53. Incubation of active p38 kinase with p53 protein caused the phosphorylation of p53 protein at serine 389 in vitro, while no phosphorylation of p53 at serine 389 was observed when p53 was incubated with activated JNK2 or ERK2. Furthermore, pretreatment of cells with SB202190 blocked the p53 DNA binding activity and p53-dependent transcription. These results strongly suggest that the p38 kinase is at least one of the most important mediators of p53 phosphorylation at serine 389 induced by UVC radiation.
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PMID:p38 kinase mediates UV-induced phosphorylation of p53 protein at serine 389. 1021 89

Phosphorylation of the p53 tumor suppressor protein is likely to play an important role in regulating its activity. Serine 15 phosphorylation of p53 leads to a stabilization of p53 by reducing its interaction with murine double minute 2, a negative regulatory partner. Recently, p53 was reported to be activated and phosphorylated at serine 15 following UV radiation. However, the signaling pathway that mediates UV-induced phosphorylation is less well characterized. Here, we provide evidence that UVB-induced phosphorylation of p53 at serine 15 is mediated directly by ERKs and p38 kinase. We find that in a mouse JB6 epidermal cell line, ERKs and p38 kinase form a complex with p53 following UVB radiation. Inhibition of ERKs or p38 kinase activity by the use of a dominant negative mutant of ERK2 or p38 kinase or their respective specific inhibitor, PD98059 or SB202190, results in abrogation of UVB-induced phosphorylation of p53 at serine 15. Strikingly, incubation of UVB-activated ERKs or p38 kinase immunoprecipitated complex with exogenous p53 shows serine 15 phosphorylation of both exogenous and co-precipitated endogenous p53 protein. Additionally, active recombinant ERK1/2 and p38 kinase but not JNKs are also able to phosphorylate p53 at serine 15 in vitro. Furthermore, pretreatment of cells with PD98059 or SB202190 blocks p53-dependent transcription activity but increases the level of p53 co-precipitated murine double minute. These results strongly suggest that both ERKs and p38 kinase have a direct role in UVB-induced phosphorylation of p53 at serine 15 in vivo.
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PMID:ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation. 1078 82

Depsipeptide, FR901228, a novel cyclic peptide inhibitor of histone deacetylase with a unique cytotoxicity profile is currently in phase I clinical trials. Here we demonstrate that, in addition to G2/M arrest, FR901228 causes G1 arrest with Rb hypophosphorylation. In vitro kinase assays demonstrated no direct inhibition of CDK activity, however, an inhibition was observed in CDKs extracted from cells exposed to FR901228. Cyclin D1 protein disappeared between 6 and 12 hours after treatment with FR901228, whereas cyclin E was upregulated. While it did not induce wt p53, FR901228 did induce p21(WAF1/CIP1)in a p53-independent manner. Cell clones lacking p21 were not arrested in G1 phase, but continued DNA synthesis and were arrested in G2/M phase following FR901228 treatment. Finally, FR901228 blunted ERK-2/MAPK activation by EGF whereas early signal transduction events remained intact since overall cellular tyrosine phosphorylation after EGF stimulation was unaffected. Thus, FR901228, while not directly inhibiting kinase activity, causes cyclin D1 downregulation and a p53-independent p21 induction, leading to inhibition of CDK and dephosphorylation of Rb resulting in growth arrest in the early G1 phase. In contrast to the G1 arrest, the G2/M arrest is p21-independent, but is associated with significant cytotoxicity.
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PMID:P21-dependent g(1)arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. 1095 88

The p53 tumor suppressor protein is a transcription factor that plays a major role in the DNA damage response. After DNA damage, p53 levels increase due primarily to stabilization of the protein. The molecular mechanisms leading to stabilization of p53 after DNA damage have not been completely elucidated. Recently we reported that cisplatin treatment activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) and that inhibition of ERK1/2 resulted in enhanced sensitivity to cisplatin. In the present study, we examined the potential role of ERK1/2 activation in regulation of the p53 response to cisplatin. In the ovarian carcinoma cell line A2780, inhibition of ERK1/2 activation with the mitogen-activated protein kinase/ERK kinase 1 (MEK1) inhibitor PD98059 resulted in decreased p53 protein half-life and diminished accumulation of p53 protein during exposure to cisplatin. We also demonstrated that p53 protein co-immunoprecipitated with ERK1/2 protein and was phosphorylated by activated recombinant murine ERK2 in vitro. Furthermore, PD98059 decreased the phosphorylation of p53 at serine 15 during cisplatin exposure, suggesting that ERK1/2 mediates in part phosphorylation of p53 during the cisplatin DNA response. These results strongly suggest that cisplatin-induced ERK activation is an up-stream regulator of the p53 response to DNA damage caused by cisplatin.
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PMID:Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin. 1095 92

Resveratrol, a phytoalexin found in grapes, berries, and peanuts, is one of the most promising agents for cancer prevention. Our previous study showed that the antitumor activity of resveratrol occurs through p53-mediated apoptosis. In this study, we have elucidated the potential signaling components underlying resveratrol-induced p53 activation and induction of apoptosis. We found that in a mouse JB6 epidermal cell line, resveratrol activated extracellular-signal-regulated protein kinases (ERKs), c-Jun NH2-terminal kinases (JNKs), and p38 kinase and induced serine 15 phosphorylation of p53. Stable expression of a dominant negative mutant of ERK2 or p38 kinase or their respective inhibitor, PD98059 or SB202190, repressed the phosphorylation of p53 at serine 15. In contrast, overexpression of a dominant negative mutant of JNKI had no effect on the phosphorylation. Most importantly, ERKs and p38 kinase formed a complex with p53 after treatment with resveratrol. Strikingly, resveratrol-activated ERKs and p38 kinase, but not JNKs, phosphorylated p53 at serine 15 in vitro. Furthermore, pretreatment of the cells with PD98059 or SB202190 or stable expression of a dominant negative mutant of ERK2 or p38 kinase impaired resveratrol-induced p53-dependent transcriptional activity and apoptosis, whereas constitutively active MEK1 increased the transcriptional activity of p53. These data strongly suggest that both ERKs and p38 kinase mediate resveratrol-induced activation of p53 and apoptosis through phosphorylation of p53 at serine 15.
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PMID:Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. 1124 72

In this study, we showed that nuclear ERK2 phosphorylates p53 at Thr55 in response to doxorubicin. p53 was found to physically interact with ERK2 as evidenced by Western blotting of ERK2 coimmunoprecipitated complex. The gene fragment encoded for N-terminal 68 amino acids was subcloned and fused with 6-His. Each serine or threonine site in this fragment, the possible phosphorylation site, was mutated to alanine. The recombinant proteins were used as substrates in ERK2 kinase assay. The results show that ERK2 phosphorylated p53 at Thr55. Further, electromobility shift assay showed that the phosphorylation of p53 by nuclear ERK2 was closely related to the transactivating activity of p53. These findings suggest that ERK2 may play a role in response to DNA damage via interaction with p53.
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PMID:Nuclear extracellular signal-regulated kinase 2 phosphorylates p53 at Thr55 in response to doxorubicin. 1140 76


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