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)

Previously we showed that cardiac fibroblasts are cellular targets of estrogen and that there are significant differences in proliferative response of male and female cardiac fibroblasts under hypoxia, a condition of myocardial ischemia. Here, we tested the hypothesis that signaling pathways that control cell cycle progression and apoptosis in cardiac fibroblasts may be activated in a gender-specific manner. Cardiac fibroblasts from adult, age-matched male and female rat heart were exposed to hypoxia (2% O2) and normoxia. Western analysis of cell lysate was used to compare the level of basal and hypoxia-induced expression of signal transduction proteins, known to control cell cycle progression and cell death. Hypoxia led to significant activation of MAP (mitogen-activated protein) kinase and Jun kinase pathways, as shown by phosphorylated extracellular signal-regulated kinase (ERK1/2) and Jun kinase isotypes in male cells but this effect was modest in female cells. Male cells expressed higher levels of basal expression for transcription factors c-jun and NF-kB as well as the inhibitor of NF-kB (lk-B). Although hypoxia did not induce changes in the level of c-Jun in either cell type, it moderately increased the level of NF-kB in male cells but led to its decrease in female cells. Basal and hypoxia-induced expression of cyclin D1, c-fos, and PCNA seemed to be comparable in both male and female cells. However, hypoxia-induced activation of cyclin B1, which occurred in both cells, was stronger in female cells. Basal expression of apoptosis-associated transcription factor, p53, was comparable in both cells. However, under hypoxia, there was an increase in the p53 level only in female cells. Although female cells showed higher basal expression for survival-associated protein, Bcl-2, the level of this protein remained unchanged under hypoxia in both cells. Together, these data demonstrate differences in basal and hypoxia-induced expression of proteins with an established role in cell cycle progression and apoptosis in male and female cardiac fibroblasts. These differences may further point to gender-related differences in signal transduction pathways that control the proliferative response of those cells under hypoxia.
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PMID:Gender-related differences in basal and hypoxia-induced activation of signal transduction pathways controlling cell cycle progression and apoptosis, in cardiac fibroblasts. 1237 61

Activation of the mitogen-activated protein kinases ERK1/2 by the chemotherapeutic agent cisplatin has been shown to result in either survival or cell death. The downstream mediators of these opposing effects are unknown, as are the upstream signaling molecules. Activation of ERK is required for accumulation and phosphorylation of p53 following cisplatin treatment. We studied the role of ERK activation after cisplatin treatment under p53-negative and p53-positive conditions using a tetracycline-dependent expression vector in Saos-2 osteosarcoma cells. Dose-dependent activation of ERK first occurred 3-6 h after a 2-h cisplatin incubation and declined after 12-24 h in several tumor cell lines. Incubation of cell lines with the MEK1 inhibitors PD98059 or UO126 after, but not during, cisplatin treatment completely inhibited cisplatin-induced activation of ERK. The activation of ERK by cisplatin was inhibited by transient transfection with dominant-negative Ras-N17 in Saos-2 cells. Treatment of cells with PD98059 or UO126 after cisplatin incubation or inhibition of signaling through ERK by tetracycline-regulated expression of dominant-inhibitory ERK enhanced resistance to cisplatin in p53-negative osteosarcoma cells and reduced cisplatin-induced apoptosis. P53 was stabilized and phosphorylated in a MEK1-dependent manner after cisplatin incubation in Kelly neuroblastoma cells. Inhibition of signaling through ERK increased cell survival after cisplatin treatment in these cells as well. Expression of functional p53 did not change the proapoptotic effects of ERK activation in response to cisplatin in Saos-2 cells. Our results suggest that cisplatin-induced activation of ERK is mediated by Ras. ERK activation increased cisplatin-induced cell death independently of p53 in osteosarcoma and neuroblastoma cell lines.
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PMID:Ras-mediated activation of ERK by cisplatin induces cell death independently of p53 in osteosarcoma and neuroblastoma cell lines. 1243 98

EB1089, a novel vitamin D3 analog, has been shown to have cytotoxic and antiproliferative properties in a variety of malignant cells. However, its potential as a treatment for B-cell chronic lymphocytic leukemia (B-CLL) has not been evaluated. EB1089 induced apoptosis in all of the 102 B-CLL samples tested with a mean LD(50) (the concentration of EB1089 required to kill 50% of cells) value (+/- SD) of 2.1 x 10(-8) M (+/- 1.4 x 10(-8) M). Furthermore, no significant difference was found in the cytotoxicity of EB1089 in B-CLL samples from previously treated and untreated patients (P =.1637). Induction of apoptosis was associated with a reduction in Bcl-2 and Mcl-1 protein expression, but this was evident only in the apoptotic cells. In contrast, the expression of Bax, p21, and p53 was not altered in the viable or apoptotic cells from either B- or T-lymphocyte lineages. EB1089-induced apoptosis was preceded by activation of p38 mitogen-activated protein (MAP) kinase and suppression of extracellular signal-regulated kinase (ERK) activity, and this was associated with downstream activation of caspase-3. The pancaspase inhibitor (Z-VAD-FMK) and the caspase-9 inhibitor (Z-LEHD-FMK) were able to partially abrogate the apoptotic effects of EB1089 but did not affect the phosphorylation of p38 MAP kinase or the suppression of ERK. The B-CLL cells in the study were shown to highly express vitamin D receptor, but an additional receptor-independent mechanism of cell killing cannot be ruled out at this stage. These findings show that EB1089 is a potent apoptosis-inducing agent in B-CLL cells and may be useful in the treatment of B-CLL patients, particularly those with p53 mutations or drug-resistant disease.
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PMID:The vitamin D3 analog EB1089 induces apoptosis via a p53-independent mechanism involving p38 MAP kinase activation and suppression of ERK activity in B-cell chronic lymphocytic leukemia cells in vitro. 1244 53

Activated pancreatic stellate cells (PSCs) have recently been implicated in the pathogenesis of pancreatic fibrosis and inflammation. Primary PSCs can be subcultured only several times because of their limited growth potential. A continuous cell line would be valuable in studying molecular mechanisms of these pancreatic disorders. The aim of this study was to establish an immortalized cell line of rat PSCs. PSCs were isolated from the pancreas of male Wistar rats, and the simian virus 40 T antigen was introduced to PSCs by retrovirus-mediated gene transfer. This procedure yielded an actively growing cell line, designated as SAM-K. This cell line has been passaged repeatedly for almost 2 years, and is thus likely immortalized. SAM-K cells retained morphological characteristics of primary PSCs, and expressed alpha-smooth muscle actin, glial fibrillary acidic protein, type I collagen, fibronectin, and prolyl hydroxylases. The level of p53 expression was very high in SAM-K cells. Proliferation of SAM-K cells was stimulated by serum and platelet-derived growth factor-BB. Interleukin-1beta (IL-1beta) activated nuclear factor-kappaB, activator protein-1, and three classes of mitogen-activated protein (MAP) kinases: extracellular signal-regulated kinase1/2, c-Jun N-terminal kinase, and p38 MAP kinase. IL-1beta induced expression of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1, both of which were abolished in the presence of pyrrolidine dithiocarbamate, a specific inhibitor of nuclear factor-kappaB activation. IL-1beta-induced monocyte chemoattractant protein-1 was partially inhibited by specific inhibitors of MAP kinase kinase (U0126) and of p38 MAP kinase (SB203580) whereas intercellular adhesion molecule-1 expression was not altered by the inhibitors. Thus, SAM-K would be useful for in vitro studies of cell biology and signal transduction of PSCs.
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PMID:Establishment and characterization of a simian virus 40-immortalized rat pancreatic stellate cell line. 1249 15

Acadesine, 5-aminoimidazole-4-carboxamide (AICA) riboside, induced apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells in all samples tested (n = 70). The half-maximal effective concentration (EC(50)) for B-CLL cells was 380 +/- 60 microM (n = 5). The caspase inhibitor Z-VAD.fmk completely blocked acadesine-induced apoptosis, which involved the activation of caspase-3, -8, and -9 and cytochrome c release. Incubation of B-CLL cells with acadesine induced the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), indicating that it is activated by acadesine. Nitrobenzylthioinosine (NBTI), a nucleoside transport inhibitor, 5-iodotubercidin, an inhibitor of adenosine kinase, and adenosine completely inhibited acadesine-induced apoptosis and AMPK phosphorylation, demonstrating that incorporation of acadesine into the cell and its subsequent phosphorylation to AICA ribotide (ZMP) are necessary to induce apoptosis. Inhibitors of protein kinase A and mitogen-activated protein kinases did not protect from acadesine-induced apoptosis in B-CLL cells. Moreover, acadesine had no effect on p53 levels or phosphorylation, suggesting a p53-independent mechanism in apoptosis triggering. Normal B lymphocytes were as sensitive as B-CLL cells to acadesine-induced apoptosis. However, T cells from patients with B-CLL were only slightly affected by acadesine at doses up to 4 mM. AMPK phosphorylation did not occur in T cells treated with acadesine. Intracellular levels of ZMP were higher in B-CLL cells than in T cells when both were treated with 0.5 mM acadesine, suggesting that ZMP accumulation is necessary to activate AMPK and induce apoptosis. These results suggest a new pathway involving AMPK in the control of apoptosis in B-CLL cells and raise the possibility of using acadesine in B-CLL treatment.
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PMID:Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes. 1252 4

p53 has a role in many cellular processes through the transcriptional regulation of target genes. PAC1 (phosphatase of activated cells 1; also known as dual specificity phosphatase 2, DUSP2) is a dual threonine/tyrosine phosphatase that specifically dephosphorylates and inactivates mitogen-activated protein (MAP) kinases. Here we show that during apoptosis, p53 activates transcription of PAC1 by binding to a palindromic site in the PAC1 promoter. PAC1 transcription is induced in response to serum deprivation and oxidative stress, which results in p53-dependent apoptosis, but not in response to gamma-irradiation, which causes cell cycle arrest. Reduction of PAC1 transcription using small interfering RNA inhibits p53-mediated apoptosis, whereas overexpression of PAC1 increases susceptibility to apoptosis and suppresses tumour formation. Moreover, activation of p53 significantly inhibits MAP kinase activity. We conclude that, under specific stress conditions, p53 regulates transcription of PAC1 through a new p53-binding site, and that PAC1 is necessary and sufficient for p53-mediated apoptosis. Identification of a palindromic motif as a p53-binding site may reveal a novel mechanism whereby p53 regulates its target genes.
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PMID:PAC1 phosphatase is a transcription target of p53 in signalling apoptosis and growth suppression. 1267 51

Resveratrol, a constituent of grapes and other foods, has been reported to be a potential cancer chemopreventive agent. Our previous study showed that the antitumor activity of resveratrol occurs through mitogen-activated protein kinases-mediated p53 activation and induction of apoptosis. To develop more effective agents with fewer side effects for the chemoprevention of cancer, we investigated the effect of resveratrol and its structurally related derivatives on epidermal growth factor (EGF)-induced cell transformation. Our results provided the first evidence that one of the resveratrol derivatives exerted a more potent inhibitory effect than resveratrol on EGF-induced cell transformation, but had less cytotoxic effects on normal nontransformed cells. Compared to resveratrol, this compound also caused cell cycle arrest in the G1 phase, but did not induce p53 activation and apoptosis. Furthermore, this compound, but not resveratrol, markedly inhibited EGF-induced phosphatidylinositol-3 kinase (PI-3K) and Akt activation. Collectively, these data suggested that the higher antitumor effect of the compound compared to resveratrol, may act through a different mechanism by mainly targeting PI-3K/Akt signaling pathways.
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PMID:Inhibition of cell transformation by resveratrol and its derivatives: differential effects and mechanisms involved. 1268 16

The negative-regulatory feedback loop between p53 and hdm2 forms part of a finely balanced regulatory network of proteins that controls cell cycle progression and commitment to apoptosis. Expression of hdm2, and its mouse orthologue mdm2, is known to be induced by p53, but recent evidence has demonstrated mdm2 expression can also be regulated via p53-independent pathways. However the p53 independent mechanisms that control transcription of the human hdm2 gene have not been studied. Differential levels of hdm2 mRNA and protein expression have been reported in several types of human malignancy, including breast cancers in which hdm2 expression correlates with positive estrogen receptor alpha (ERalpha) status. Experimental models have demonstrated that hdm2 overexpression can promote breast cancer development. Here, we show that the elevated level of hdm2 protein in ERalpha(+ve) breast cancer cell lines such as MCF-7 and T47D is because of transcription from the p53-inducible P2 promoter of hdm2. The P2 promoter is inactive in ERalpha(-ve) cell lines such as SKBr3. Hdm2-P2 promoter activity in T47D cells is independent of p53, as well as of known regulators of the mouse mdm2-P2 promoter, including ERalpha and ras-raf-mitogen-activated protein/extracellular signal-regulated kinase (MEK) mitogen-activated protein kinase (MAPK) signaling. We show that hdm2-P2 activity in T47D cells is dependent on the integrity of both an evolutionarily conserved composite binding site for AP1 and ETS family transcription factors (AP1-ETS) and a nonconserved upstream (nnGGGGC)(5) repeat sequence. Lack of hdm2-P2 activity in ERalpha(-ve) cells is shown to be a consequence of reduced transcriptional activation through the AP1-ETS element. Overexpression of ETS2 in SKBr3 cells reconstitutes AP1-ETS element-dependent hdm2-P2 promoter activity, resulting in increased levels of hdm2 protein in the cells. Our findings support the hypothesis that the elevated levels of hdm2 expression reported in cancers such as ERalpha(+ve) breast tumors play an important role in the development of these tumors.
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PMID:p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells. 1275 Feb 88

Results of past space experiments suggest that the biological effect of space radiation could be enhanced under microgravity in some cases, especially in insects. To examine if such a synergistic effect of radiation and microgravity also exists in human cells, frequencies of chromosome instability and cellular levels of several stress-responsive proteins were analyzed in cultured human and rodent cells after space flight. Human (MCF7 and AT2KY), mouse (m5S) and hamster (SHE) cell lines were loaded on the Space Shuttle Discovery (STS-95 mission) and grown during a 9-day mission. After landing, the micronuclei resulting from abnormal nuclear division and accumulation of stress-responsive proteins such as p53 and mitogen-activated protein kinases (MAPKs), which are involved in radiation-induced signal transduction cascades, were analyzed. The frequencies of micronuclei in all the four mammalian cell strains tested were not significantly different between flight and ground control samples. Also, the cellular amounts of p53, p21 (WAF1/SDI1/CIP1) and activated (phosphorylated) forms of three distinct MAPKs in MCF7 and m5S cells of flight samples were similar to those of ground control samples. These results indicated that any effect of space radiation, microgravity, or combination of both were not detectable, at least under the present experimental conditions.
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PMID:Effect of space flight on the frequency of micronuclei and expression of stress-responsive proteins in cultured mammalian cells. 1279 48

Assessment of specific apoptosis and survival pathways implicated in anticancer drug action is important for understanding drug mechanisms and modes of resistance in order to improve the benefits of chemotherapy. In order to better examine the role of mitogen-activated protein kinases, including JNK and ERK, as well as the tumor suppressor p53, in the response of tumor cells to chemotherapy, we compared the effects on these pathways of three structurally and functionally distinct antitumor agents. Drug concentrations equal to 50 times the concentration required to reduce cell proliferation by 50% were used. Vinblastine, doxorubicin, or etoposide (VP-16) induced apoptotic cell death in KB-3 carcinoma cells, with similar kinetic profiles of PARP cleavage, caspase 3 activation, and mitochondrial cytochrome c release. All three drugs strongly activated JNK, but only vinblastine induced c-Jun phosphorylation and AP-1 activation. Inhibition of JNK by SP600125 protected cells from drug-induced cytotoxicity. Vinblastine caused inactivation of ERK whereas ERK was unaffected in cells exposed to doxorubicin or VP-16. Inhibition of ERK signaling by the MEK inhibitor, U0126, potentiated the cytotoxic effects of vinblastine and doxorubicin, but not that of VP-16. Vinblastine induced p53 downregulation, and chemical inhibition of p53 potentiated vinblastine-induced cell death, suggesting a protective effect of p53. In contrast, doxorubicin and VP-16 induced p53, and inhibition of p53 decreased drug-induced cell death, suggesting a pro-apoptotic role for p53. These results highlight the differential roles played by several key signal transduction pathways in the mechanisms of action of key antitumor agents, and suggest ways to specifically potentiate their effects in a context-dependent manner. In addition, the novel finding that JNK activation can occur without c-Jun phosphorylation or AP-1 activation has important implications for our understanding of JNK function.
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PMID:The JNK, ERK and p53 pathways play distinct roles in apoptosis mediated by the antitumor agents vinblastine, doxorubicin, and etoposide. 1290 45


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