Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 tumour suppressor protein is tightly regulated by protein-protein association, protein turnover and a variety of post-translational modifications. Multisite phosphorylation plays a major role in activating and in finely tuning p53 function. The proline rich domain of murine p53 is a substrate for phosphorylation, in vitro and in cultured cells, by the p42ERK2 and p44ERK1 mitogen-activated protein (MAP) kinases. However, to date there have been no reports of attempts to determine whether p53 from any other species is a substrate for MAP kinase. In this paper we confirm that murine p53 is targeted by recombinant MAP kinase and by MAP kinases in extracts of both murine and human cells. In contrast, human p53 is not a substrate for recombinant MAP kinase nor are there any detectable levels of protein kinase activity in stimulated human cell extracts which phosphorylate the proline rich domain of human p53 in vitro. Finally, although stimulation of murine fibroblasts with o-tetradecanolylphorbol 13-acetate (TPA), an indirect activator of the MAP kinase pathway, leads to site-specific phosphorylation of murine p53, similar treatment of human fibroblasts and epithelial cells showed no significant changes in the phosphorylation pattern. These data are consistent with accumulating evidence that significant species-dependent differences exist in the post-translational modification of p53.
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PMID:Phosphorylation of murine p53, but not human p53, by MAP kinase in vitro and in cultured cells highlights species-dependent variation in post-translational modification. 1060 21

An increasing number of studies indicate that cysteine cathepsins contribute to cancer progression, invasion, and metastasis. Here we provide experimental evidence that the cathepsin inhibitor Z-Phe-Gly-NHO-Bz induces rapid apoptotic death in human cancer cell lines. Notably, the Z-Phe-Gly-NHO-Bz-induced apoptosis exhibited independence of p53, caspases, and mitogen-activated protein (MAP) kinases. Taken together, our results prompt the hypothesis that cysteine cathepsin(s) is a universal survival factor for cancer cells, and its inhibition leads to cancer cell apoptosis. The exquisite sensitivity of human cancer cells to CATI-1 indicates that this compound and its derivatives may provide the basis for new treatment programs against a broad spectrum of malignancies.
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PMID:Z-Phe-Gly-NHO-Bz, an inhibitor of cysteine cathepsins, induces apoptosis in human cancer cells. 1081 33

Proteasome inhibition leads to accumulation of transcription factors, heat shock proteins, cyclins, and other proteasome substrate proteins by blocking their proteolytic degradation. An increase in gene transcription upon proteasome inhibition was found for a group of proteins, including p21(WAF1/CIP1), ubiquitin, and transcription factors. In this study, we have demonstrated selective up-regulation of extracellular signal-regulated kinase 3 (ERK3) mRNA and protein expression upon treatment with peptide-based proteasome inhibitors or lactacystin. ERK3 is a family member of the mitogen-activated protein kinases (also called ERK) that are key mediators of signal transduction from the cell surface to the nucleus. ERK3 up-regulation is independent of the p53, Bcl2, and caspase 3 status of cells. p38 pathway kinase inhibitors prevent proteasome-dependent ERK3 induction and enhance the antiproliferative effect of proteasome inhibitors. MCF-7 cells expressing ERK3 ectopically show increased resistance toward proteasome inhibition. The results indicate that ERK3 expression is a consequence of p38 pathway activation and most probably represents an intracellular defense or rescue mechanism against cell stress and damage induced by proteasome inhibition.
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PMID:Proteasome- and p38-dependent regulation of ERK3 expression. 1114 4

We have previously reported that apigenin inhibits the growth of thyroid cancer cells by attenuating epidermal growth factor receptor (EGF-R) tyrosine phosphorylation and phosphorylation of ERK mitogen-activated protein (MAP) kinase. In this study, we assessed the growth inhibitory effect of apigenin on MCF-7 breast carcinoma cells that express two key cell cycle regulators, wild-type p53 and the retinoblastoma tumor suppressor protein (Rb), and MDA-MB-468 breast carcinoma cells that are mutant for p53 and Rb negative. We found that apigenin potently inhibited growth of both MCF-7 and MDA-MB-468 breast carcinoma cells. The approximate IC50 values determined after 3 days incubation, were 7.8 micrograms/ml for MCF-7 cells, and 8.9 micrograms/ml for MDA-MB-468 cells, respectively. Because the cell cycle studies using FACS showed that both MCF-7 and MDA-MB-468 cells were arrested in G2/M phase after apigenin treatment, we studied the effects of apigenin on cell cycle regulatory molecules. We observed that G2/M arrest by apigenin involved a significant decrease in cyclin B1 and CDK1 protein levels, resulting in a marked inhibition of CDK1 kinase activity. Apigenin reduced the protein levels of CDK4, cyclins D1 and A, but did not affect cyclin E, CDK2 and CDK6 protein expression. In MCF-7 cells, apigenin markedly reduced Rb phosphorylation after 12 h. We also found that apigenin treatment resulted in a dose- and time-dependent inhibition of ERK MAP kinase phosphorylation and activation in MDA-MB-468 cells. These results suggest that apigenin is a promising antibreast cancer agent and its growth inhibitory effects are mediated by targeting different signal transduction pathways in MCF-7 and MDA-MB-468 breast carcinoma cells.
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PMID:Apigenin inhibits growth and induces G2/M arrest by modulating cyclin-CDK regulators and ERK MAP kinase activation in breast carcinoma cells. 1129 71

When MCF-7 cells were incubated with 10 or 20 microM CdCl(2), p53 protein level increased after 18 h. Among serines in p53 protein immunoprecipitated from cells treated with CdCl(2), only Ser 15 was phosphorylated. No clear phosphorylation was found on Ser 6, 9, 20, 37, and 392. Accumulation of p53 protein phosphorylated at Ser 15 was also found after 18 h exposure. While phosphorylation of extracellular signal-regulated protein kinase, c-Jun NH2-terminal kinase and p38 was found in cells treated with CdCl(2), treatment with U0126, LL-Z1640-2, or SB203580 did not suppress Ser 15 phosphorylation. On the other hand, treatment with wortmannin or caffeine suppressed CdCl(2)-induced Ser 15 phosphorylation and accumulation of p53 protein. The present results showed that cadmium induces phosphorylation of p53 at Ser 15 in MCF-7 cells depending on phosphatidylinositol 3-kinase related kinases, but not on mitogen-activated protein kinases.
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PMID:Cadmium induces phosphorylation of p53 at serine 15 in MCF-7 cells. 1130 31

The anti-cancer agent paclitaxel (Taxol) stabilizes microtubules leading to G2/M cell cycle arrest and apoptotic cell death. In order to analyse the molecular mechanisms of Taxol-induced cytotoxicity, we studied the involvement of mitogen-activated protein kinases (MAPK) ERK and p38 as well as the p53 pathways in Taxol-induced apoptosis. The human breast carcinoma cell line MCF7 and its derivatives, MCF7/HER-2 and MDD2, were used in the study. We found that Taxol treatment strongly activated ERK, p38 MAP kinase and p53 in MAP kinase MCF7 cells prior to apoptosis. PD98059 or SB203580, specific inhibitors of ERK and p38 kinase activities, significantly decreased apoptosis, leaving the surviving cells arrested in G2/M. These inhibitors did not significantly affect Taxol-induced alterations in the cell cycle regulatory proteins Rb, p53, p21/Waf1 and Cdk-2. In addition, inactivation of p53 did not affect cellular sensitivity to Taxol killing. However, cells with inactivated p53, unlike cells harboring wild type p53, failed to arrest in G2/M after treatment with Taxol and continued to divide or go into apoptosis. Our data show that both ERK and p38 MAP kinase cascades are essential for apoptotic response to Taxol-induced cellular killing and are independent of p53 activity. However, p53 may serve as a survival factor in breast carcinoma cells treated with Taxol by blocking cells in G2/M phase of the cell cycle.
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PMID:Taxol-induced apoptosis depends on MAP kinase pathways (ERK and p38) and is independent of p53. 1131 44

We demonstrated here that X-ray irradiation at very low doses of between 2 and 5 cGy stimulated proliferation of normal human diploid cells and human tumor cells. Higher doses of irradiation at >1 Gy accumulated p53 protein and induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Phosphorylation of ERK1/2 decreased with dose down to 50 cGy, however, doses of between 5 cGy and 2 cGy phosphorylated ERK1/2 as efficiently as higher doses of X-rays, whereas the p53 protein level was not changed by doses <50 cGy. We found that mitogen-activated protein /ERK kinase (MEK) 1 was phosphorylated with both 2 cGy and 6 Gy of X-rays, and that activated ERK1/2 augmented phosphorylation of Elk-1 protein. The specific epidermal growth factor receptor tyrosine kinase inhibitor, AG1478, decreased phosphorylation of the ERK1/2 proteins induced by 2 cGy or 6 Gy of X-rays, and similar suppressive effect was observed with MEK inhibitor, PD98059. Suppression of ERK1/2 phosphorylation with these inhibitors alleviated enhanced proliferation of normal human cells by low-dose irradiation. Furthermore, overexpression of ERK2 in NCI-H1299 human lung carcinoma cells potentiated enhanced proliferation, whereas down-regulation of ERK2 using the antisense ERK2 gene abrogated the stimulative effect of low-dose irradiation. These results indicate that a limited range of low-dose ionizing radiation differentially activates ERK1/2 kinases via activation of epidermal growth factor receptor and MEK, which causes enhanced proliferation of cells receiving very low doses of ionizing radiation.
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PMID:Extremely low-dose ionizing radiation causes activation of mitogen-activated protein kinase pathway and enhances proliferation of normal human diploid cells. 1145 82

The p53-regulated stress-inducible gene GADD45 has been shown to participate in cellular response to DNA damage, including cell cycle checkpoint, apoptosis, and DNA repair. However, the regulation of GADD45 expression is complex and may involve both p53-dependent and -independent pathways. Recent findings have demonstrated that the p53-independent induction of GADD45 is mainly regulated by the transcription factors Oct-1 and NF-YA, which directly bind to their consensus motifs located at the GADD45 promoter region. Here, we report that mitogen-activated protein (MAP) kinases are involved in the induction of the GADD45 promoter after DNA damage. Inhibition of JNK1 and ERK kinase activities either by expression of the dominant negative mutant JNK1 or by treatment with a selective chemical inhibitor of ERK (PD098059) substantially abrogates the UV induction of the GADD45 promoter. In contrast, a p38 kinase inhibitor (SB203580) has little effect on GADD45 induction by UV. In addition, the GADD45 promoter is strongly activated following expression of JNK1; Raf-1, which is an upstream activator of the ERK pathway; or MEK1, an upstream activator of both the ERK and the JNK pathways. Activation of the GADD45 promoter by MAP kinases does not require normal p53 function. Interestingly, the MAP kinase-regulatory effect appears to be mediated via OCT-1 and CAAT motifs since disruption of these sites abrogates activation of the GADD45 promoter by MAP kinases. Therefore, these findings indicate that the MAP kinase pathways are involved in the regulation of the p53-independent induction of the GADD45 promoter, probably via interaction with transcription factors that directly bind to OCT-1 and CAAT motifs.
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PMID:Involvement of the MAP kinase pathways in induction of GADD45 following UV radiation. 1152 40

Signals from the extracellular matrix are essential for the survival of many cell types. Dominant-negative mutants of two members of Rho family GTPases, Rac1 and Cdc42, mimic the loss of anchorage in primary mouse fibroblasts and are potent inducers of apoptosis. This pathway of cell death requires the activation of both the p53 tumor suppressor and the extracellular signal-regulated mitogen-activated protein kinases (Erks). Here we characterize the proapoptotic Erk signal and show that it differs from the classically observed survival-promoting one by the intensity of the kinase activation. The disappearance of the GTP-bound forms of Rac1 and Cdc42 gives rise to proapoptotic, moderate activation of the Raf-MEK-Erk cascade via a signaling pathway involving the kinases phosphatidlyinositol 3-kinase and Akt. Moreover, concomitant activation of p53 and inhibition of Akt are both necessary and sufficient to signal anoikis in primary fibroblasts. Our data demonstrate that the GTPases of the Rho family control three major components of cellular signal transduction, namely, p53, Akt, and Erks, which collaborate in the induction of apoptosis due to the loss of anchorage.
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PMID:Raf-MEK-Erk cascade in anoikis is controlled by Rac1 and Cdc42 via Akt. 1153 57

To determine whether enzymatic p53 glycosylation leads to angiotensin II formation followed by p53 phosphorylation, prolonged activation of the renin-angiotensin system, and apoptosis, ventricular myocytes were exposed to levels of glucose mimicking diabetic hyperglycemia. At a high glucose concentration, O-glycosylation of p53 occurred between 10 and 20 min, reached its peak at 1 h, and then decreased with time. Angiotensin II synthesis increased at 45 min and 1 h, resulting in p38 mitogen-activated protein (MAP) kinase-driven p53 phosphorylation at Ser 390. p53 phosphorylation was absent at the early time points, becoming evident at 1 h, and increasing progressively from 3 h to 4 days. Phosphorylated p53 at Ser 18 and activated c-Jun NH(2)-terminal kinases were identified with hyperglycemia, whereas extracellular signal-regulated kinase was not phosphorylated. Upregulation of p53 was associated with an accumulation of angiotensinogen and AT(1) and enhanced production of angiotensin II. Bax quantity also increased. These multiple adaptations paralleled the concentrations of glucose in the medium and the duration of the culture. Myocyte death by apoptosis directly correlated with glucose and angiotensin II levels. Inhibition of O-glycosylation prevented the initial synthesis of angiotensin II, p53, and p38-MAP kinase (MAPK) phosphorylation and apoptosis. AT(1) blockade had no influence on O-glycosylation of p53, but it interfered with p53 phosphorylation; losartan also prevented phosphorylation of p38-MAPK by angiotensin II. Inhibition of p38-MAPK mimicked at a more distal level the consequences of losartan. In conclusion, these in vitro results support the notion that hyperglycemia with diabetes promotes myocyte apoptosis mediated by activation of p53 and effector responses involving the local renin-angiotensin system.
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PMID:Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death. 1157 21


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