Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the MEK/ERK/MAP kinase signaling pathway promotes the proliferation and survival of hematopoietic cells. The kinases MEK-1, MEK-2, ERK-1/MAPK and ERK-2/MAPK are activated by phosphorylation at specific sites, and these events can be monitored using phospho-specific antibodies. In this report we examined the importance of the MEK/ERK/MAP kinase pathway in the monocytic and granulocytic differentiation of myeloid cell lines. Induction of monocytic differentiation in HL-60 cells by treatment with phorbol 12-myristate 13-acetate (PMA) led to rapid and sustained activation of MEK-1/-2, ERK-1/MAPK and ERK-2/MAPK, while induction of granulocytic differentiation by retinoic acid (RA) caused similar activation of MEK-1/-2 and ERK-2/MAPK, but not ERK-1/MAPK. The total levels of these kinases were not affected during the course of differentiation along either pathway. Pretreatment of cells with 5 microM of the MEK-1/-2-specific inhibitor U0126 abrogated PMA- or RA-induced activation of ERK-1/MAPK and ERK-2/MAPK. Importantly, pretreatment of HL-60 cells with U0126 was found to potently inhibit both monocytic and granulocytic differentiation, as assessed by cytochemical staining for non-specific esterase or nitroblue tetrazolium reduction, flow cytometric analysis of myeloid surface markers, and immunoblotting for the cell cycle inhibitor p21 WAF1/Cip1. Similar results were seen in U937 cells, where U0126 inhibited PMA-induced monocytic differentiation, and in 32D cells, where G-CSF-induced granulocytic differentiation was inhibited by U0126 pretreatment. Additional experiments revealed that inhibition of MEK-1/-2 in HL-60 cells resulted in nearly complete inhibition of differentiation-induced cell death during monocytic differentiation. By contrast, U0126 only partially inhibited cell death resulting from granulocytic differentiation. Taken together, our findings demonstrate that the MEK/ERK/MAP kinase signaling pathway is activated, and plays a critical role, during both monocytic and granulocytic differentiation of myeloid cell lines.
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PMID:Importance of MEK-1/-2 signaling in monocytic and granulocytic differentiation of myeloid cell lines. 1196 Mar 50

Acrylonitrile (ACN) is a compound widely used in the synthesis of a variety of organic products. It has been found that ACN is carcinogenic in rats, and some epidemiological studies also suggest a possible carcinogenic effect of ACN in humans. The aim of the present study was to assess the effect of ACN exposure on the expression of p53 and p21(WAF1) proteins in vitro as well as in vivo. In vitro ACN exposure of human lung fibroblasts resulted in the induction of both p53 and p21(WAF1) proteins. To evaluate the effect of ACN on the levels of p53 and p21(WAF1) proteins in the blood plasma of ACN-exposed workers, samples from 49 subjects (average age 44 years, 88% males, 12% females) exposed to ACN in the petrochemical industry (ACN concentration ranged from 0.05 to 0.3mg/m(3)) were analyzed. Subjects living in the same area (N=24, average age 43 years, 92% males, 8% females), but not working in the petrochemical industry were used as controls. No significant differences in either p53, or p21(WAF1) levels between the exposed and control groups were found. The expression of p53 was significantly higher in exposed non-smokers as compared with smokers (P=0.02). No effect of GSTM1 and GSTT1 genotypes on the expression of either protein was observed. Subjects with an EPHX high activity genotype had significantly higher p21(WAF1) expression as compared with genotypes with low or medium EPHX activity. We conclude that plasma levels of both proteins are not relevant biomarkers for occupational ACN exposure.
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PMID:Acrylonitrile exposure: the effect on p53 and p21(WAF1) protein levels in the blood plasma of occupationally exposed workers and in vitro in human diploid lung fibroblasts. 1203 25

Cellular response to oxidative stress is a complex process that is often connected to cell cycle regulation. The present study examines the effect of H(2)O(2) on cell cycle regulation and involvement of reactive oxygen species (ROS) in these H(2)O(2)-induced responses in a p53-deficient human lung carcinoma cell line, H1299. Treatment of the cells with H(2)O(2) caused a G2/M phase arrest. Among the redox-sensitive transcription factors, NF-kappaB and AP-1, we found that only AP-1 was activated by 200 microM H(2)O(2) in human lung cells. Furthermore, electrophoretic mobility shift assays revealed that H(2)O(2) enhanced the DNA binding of AP-1 to a putative AP-1 binding element (TGAGGAA) in the p21(WAF1/CIP1) promoter region (between -2203 and -2197 nucleotides upstream of the transcription initiation site). An increase in c-Jun phosphorylation by ERK was also found to accompany the increased AP-1 activity as detected by Western blot. PD98059, a specific inhibitor of MEK, diminished H(2)O(2)-induced phosphorylation of c-Jun and DNA binding activity of AP-1, decreased expression of p21(WAF1/CIP1), and released the cells from G2/M arrest. Taken together, these results revealed a novel AP-1 binding site in the promoter region of p21(WAF1/CIP1) and a possible cell cycle regulation mechanism mediated by activation of a redox-dependent ERK signaling pathway.
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PMID:H(2)O(2)-induced AP-1 activation and its effect on p21(WAF1/CIP1)-mediated G2/M arrest in a p53-deficient human lung cancer cell. 1205 10

The phosphatidylinositol-3-OH kinase (PI-3K)/Akt signaling pathway plays a critical role in tumorigenesis. This pathway is activated by the amplification or overexpression of HER2/neu, which occurs in 30% of human breast and ovarian cancers. The recent identification of a number of Akt substrates suggests that Akt can enhance cell proliferation and inhibit apoptosis. In this review we will discuss the theme of action of Akt in regulating the cellular localization of its substrates to control proliferation and apoptosis in light of two new identified Akt substrates, p21(Cip1/WAF1) and MDM2.
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PMID:Novel targets of Akt, p21(Cipl/WAF1), and MDM2. 1213 99

Zinc is an important trace element in the body and is involved in both the proliferation and growth arrest of many kinds of cells including colorectal epithelial cells. The aim of this study was to identify the molecular mechanism of the growth regulation of colorectal cancer cells by extracellular zinc. Zinc-stimulated activation of the mitogen-activated protein kinase (MAPK) cascade was measured by immunoblotting and Elk-1 dependent trans-reporter gene expression, and zinc-stimulated p21(Cip/WAF1) activation by immunoblotting, Northern blot analysis and immunochemistry. Cell proliferation was measured by thymidine and bromodeoxyuridine (BrdU) incorporation. By treating colorectal cancer cells with 100 microM ZnCl2, MAPKs were activated in two different phases, the initial weak activation occurred within 5 min and this was followed by a stronger and more prolonged activation. Zinc concomitantly activated Raf-1-MEK-MAPK kinases, and induced Elk-1 dependent trans-reporter gene expression. Prolonged activation of MAPKs by 100 microM of ZnCl2 resulted in the induction and nuclear localization of p21(Cip/WAF1) and was related to the inhibition of both thymidine and BrdU incorporations. These results not only suggest the presence of a mechanism for p21(Cip/WAF1) dependent negative regulation of colorectal cancer cell growth by zinc but also suggest potential usage of zinc to control the growth of colorectal cancer cells.
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PMID:Extracellular zinc stimulates ERK-dependent activation of p21(Cip/WAF1) and inhibits proliferation of colorectal cancer cells. 1238 73

Transformation by oncogenic Ras requires signaling through Rho family proteins including RhoA, but the mechanism(s) whereby oncogenic Ras regulates the activity of RhoA is (are) unknown. We examined the effect of Ras on RhoA activity in NIH 3T3 cells either stably transfected with H-Ras(V12) under control of an inducible promoter or transiently expressing the activated H-Ras. Using a novel method to quantitate enzymatically the GTP bound to Rho, we found that expression of the oncogenic Ras increased Rho activity approximately 2-fold. Increased Rho activity was associated with increased plasma membrane binding of RhoA and decreased activity of the Rho/Ras-regulated p21(WAF1/CIP1) promoter. RhoA activation by oncogenic Ras could be explained by a decrease in cytosolic p190 Rho-GAP activity and translocation of p190 Rho-GAP from the cytosol to a detergent-insoluble cytoskeletal fraction. Pharmacologic inhibition of the Ras/Raf/MEK/ERK pathway prevented Ras-induced activation of RhoA and translocation of p190 Rho-GAP; expression of constitutively active Raf-1 kinase or MEK was sufficient to induce p190 Rho-GAP translocation. We conclude that in NIH 3T3 cells oncogenic Ras activates RhoA through the Raf/MEK/ERK pathway by decreasing the cytosolic activity and changing the subcellular localization of p190 Rho-GAP.
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PMID:Oncogenic Ras leads to Rho activation by activating the mitogen-activated protein kinase pathway and decreasing Rho-GTPase-activating protein activity. 1242 40

We previously reported that overexpression of the HER2/NEU oncogene induces all-TRANS retinoic acid (ATRA) resistance in breast cancer cells. N-(4-hydroxyphenyl)-retinamide (4HPR), a synthetic analogue of ATRA, has been shown to repress the expression of HER2/neu and its family member, epidermal growth factor receptor (EGFR). We investigated whether 4HPR, by suppressing HER2/neu or EGFR expression, could sensitize breast cancer cells to ATRA. At 1.3 micro M concentration (a clinically pharmacologically achievable dose), 4HPR increased ATRA sensitivity synergistically in HER2/NEU-overexpressing BT-474, MDA-MB-453, and MCF-7/Her2 breast cancer cells. However, 4HPR did not sensitize EGFR-overexpressing MDA-MB-468, Hs578T, and MCF-7/EGFR breast cancer cells to ATRA. The increased inhibitory effects in HER2/NEU-overexpressing cells were not correlated with increases in expression levels of p21(WAF1/CIP1) or retinoblastoma protein. Combining 4HPR with ATRA may lead to a novel, selective therapeutic or chemopreventive strategy against HER2/NEU-overexpressing breast tumors.
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PMID:N-(4-hydroxyphenyl)-retinamide selectively increases All-TRANS retinoic acid inhibitory effects in HER2/NEU-overexpressing breast cancer cells. 1259 44

Differentiation therapy for myeloid leukemia offers great potential as a supplement to the current treatment modalities. In the present report, we investigated if the pyranocoumarins, (+/-)-4'- O-acetyl-3'- O-angeloyl- cis-khellactone (or angular pyranocoumarin, APC) isolated from the medicinal plant Peucedanum praeruptorum Dunn, could induce human acute myeloid leukemic HL-60 cells to differentiate and elucidated the molecular mechanism(s) involved. The ability of HL-60 cells to reduce nitroblue tetrazolium (NBT) was significantly increased after APC treatment for 72 h. In these differentiating HL-60 cells, cell surface differentiation markers CD11b (for myeloid cells) and CD14 (for monocytic cells) were detected in 90.3 % and 70.1 % of the cells, respectively. The differentiation inducing effect of APC was time- and dose-dependent. Treatment with 20 microg/mL APC for 72 h inhibited cell growth by 90 % and cell cycle analysis revealed an increase in the proportion of G1 phase cells. In these growth-inhibited cells the expression of the cyclin-dependent kinase inhibitor p27 kip1, but not p21 WAF1, was up-regulated as shown by Western blotting. Differentiation inducing signal pathways were investigated and it was shown that phospho-MEK and phospho-ERK were elevated shortly after the addition of APC. Pre-incubation of the cells with MEK1 inhibitor PD98059 blocked this APC-induced differentiation. Our results suggest that APC are potent inducers of HL-60 cell differentiation along both the myelocytic and monocytic lineages and are potential agents for differentiation-treatment of leukemia.
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PMID:Pyranocoumarins isolated from Peucedanum praeruptorum as differentiation inducers in human leukemic HL-60 cells. 1267 25

We provide here evidence that c-Jun N-terminal protein kinase 1 (JNK1) activity is differentially up-regulated during apoptosis of SK-HEP-1 cells after treatment with ginsenoside Rh2 (G-Rh2). The G-Rh2-mediated JNK1 activation that occurred for the first 10-30min was associated with SEK1 activity, but thereafter, the sustained activation was associated not with SEK1 activity, but with proteolytic cleavage of JNK1-associated p21(WAF1/CIP1). Supporting this is that the expression of the dominant negative SEK1 mutant effectively blocked the early JNK1 activation phase but did not alter the sustained activation phase or apoptosis. Furthermore, expression of p21D112N, an uncleavable mutant of p21(WAF1/CIP1), suppressed the later JNK1 activation. Moreover, the stable overexpression of ectopic JNK1 suppressed apoptosis while expression of the dominant negative JNK1 mutant promoted it. We propose that the early SEK1-associated JNK1 activation phase acts to prolong cell survival in response to apoptosis-inducing agents, thereby serving as an intervening checkpoint prior to the commitment to apoptosis.
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PMID:SEK1-dependent JNK1 activation prolongs cell survival during G-Rh2-induced apoptosis. 1271 23

Continuous fibroblast growth factor signaling inhibits the differentiation of primary osteoblasts and osteoblastic cell lines. We studied the expression of several cell cycle regulatory molecules in response to fibroblast growth factor, and found that fibroblast growth factor strongly upregulates the expression of p21(WAF1/CIP1), a CDK inhibitor that has also been implicated in the regulation of apoptosis and cell differentiation. To test the hypothesis that p21 mediated the fibroblast growth factor effects on osteoblasts, we studied the differentiation of primary osteoblasts and osteoblastic cell lines derived from p21 null mice in the presence or absence of fibroblast growth factor. While the results obtained indicate that p21 is not the major mediator of the inhibition of osteoblast differentiation by fibroblast growth factor, we found that p21 per se acts as a brake on osteoblast proliferation and differentiation. p21 is strongly downregulated during differentiation and is highly expressed in osteoblastic cell lines expressing activated FGFR2, which do not differentiate. p21 null osteoblasts differentiate faster than wild-type cells, are more susceptible to the differentiation-promoting action of BMP-2, and undergo increased differentiation-related apoptosis. Furthermore, transient overexpression of p21 from an adenovirus vector delayed the onset of differentiation both in wild-type and in p21 null osteoblasts. These results highlight a new function for p21 in osteoblast differentiation.
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PMID:p21(WAF1/CIP1) acts as a brake in osteoblast differentiation. 1273 20


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