Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The effects of vinorelbine and paclitaxel on the activity of extracellular signal-regulated protein kinase2 (ERK2), a member of MAP kinase, and its role in the induction of bcl-2 phosphorylation and apoptosis were evaluated in MCF-7 cells. We demonstrated that ERK2 was activated rapidly by vinorelbine, and was inhibited by either paclitaxel or estramustine. A 3-fold increase of ERK2 kinase activity was observed within 30 min when MCF-7 cells were treated with 0.1 microM vinorelbine. In contrast, the same treatment with paclitaxel resulted in a significant decrease of ERK2 kinase activity. We also demonstrated that elevated bcl-2 phosphorylation induced by vinorelbine is paralleled by decrease of a complex formation between bcl-2 and bax, cleavage of poly (ADP) ribose polymerase (PARP) protein, activation of caspase-7, and apoptosis. The levels of bcl-2 phosphorylation, bax, and PARP were not significantly affected by 2'-amino-3'-methoxyflavone (PD 98059), an ERK kinase specific inhibitor. Thus, our data suggest that the apoptosis induced by vinorelbine in MCF-7 cells is mediated through the bcl-2 phosphorylation/bax/caspases pathways, and that activation of ERK2 by vinorelbine does not directly lead to the drug-mediated apoptosis. Since decrease of PARP occurred quickly following the treatment of MCF-7 cells with either 0.1 microM of vinorelbine or paclitaxel, this protein may serve as an early indicator of apoptosis induced not only by DNA damaging agents, but also by antimicrotubule drugs.
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PMID:Differential effect of vinorelbine versus paclitaxel on ERK2 kinase activity during apoptosis in MCF-7 cells. 1172 Apr 82

The effects of all-trans retinoic acid on the differentiation and proliferation of immature melanocyte precursors were studied. NCC-melb4 cells are an immortal cloned cell line established from mouse neural crest cells using a single-cell cloning method. These cells were positive for tyrosinase-related protein 1, tyrosinase-related protein 2 and KIT, but were negative for tyrosinase and had no dihydroxyphenylalanine reaction. They contained only stage I melanosomes without any melanosomes in more advanced stages. After treatment with all-trans retinoic acid, many of the cells became tyrosinase- and dihydroxyphenylalanine-reaction-positive, changed from polygonal to dendritic in shape, and had stage III to IV melanosomes. These findings indicate that treatment with all-trans retinoic acid induced the differentiation of NCC-melb4 cells. Reverse transcription polymerase chain reaction analysis revealed a marked increase in expression of microphthalmia-associated transcription factor mRNA after all-trans retinoic acid treatment, suggesting that microphthalmia-associated transcription factor may be the key molecule in this event. Enhanced expression of protein kinase Calpha following treatment with all-trans retinoic acid was also demonstrated. The proliferation of NCC-melb4 cells was inhibited by all-trans retinoic acid in a dose-dependent manner. Increased apoptosis after all-trans retinoic acid treatment was observed by electron microscopy, the TUNEL method, DNA fragmentation assay, and flow cytometry. All-trans retinoic acid upregulated caspase-3 and downregulated bcl-2. Electron microscopy showed that apoptotic cells contained melanosomes of advanced stages, suggesting that mature melanocytes may tend to undergo apoptosis after all-trans retinoic acid treatment. This study provides important clues towards understanding the roles and working mechanisms of retinoic acids in melanocyte development and melanogenesis.
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PMID:All-trans retinoic acid induces differentiation and apoptosis of murine melanocyte precursors with induction of the microphthalmia-associated transcription factor. 1185 73

Early growth response gene 1 (Egr1) codes for a transcriptional regulator that contains a zinc-finger DNA binding domain. Egr1 expression is induced by a variety of extracellular stimuli including TCR-ligand interactions. Its pattern of expression in the thymus and dependence on ERK activation have led to speculation that it has a role in T cell development, but the exact nature of this role has been undefined. To more clearly define the role of Egr1 in thymocyte development, we have analyzed thymocytes from Egr1-deficient mice. We find that thymuses from Egr1-deficient mice contain twice as many cells as age-matched controls, and the increase in thymocyte number is apparent at the early CD4/CD8 double negative stage of development. Subsequent maturation to the CD4/CD8 double positive stage and survival of the double positive cells both appear normal in Egr1-deficient animals. We also find that Egr1 promotes positive selection of both CD4 and CD8 single positive cells without playing a major role in negative selection. Egr1 influences positive selection by enhancing expression of the helix-loop-helix inhibitor Id3 and the anti-apoptosis molecule bcl-2. Thus, Egr1 translates developmental signals into appropriate changes in gene expression at multiple stages of thymocyte development.
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PMID:Thymocyte development in early growth response gene 1-deficient mice. 1216 91

Epidemiologic data suggest that low exposure to vitamin D or 1alpha,25-dihydroxycholecalciferol (calcitriol) increases the risk of prostate cancer. Calcitriol, a central factor in bone and mineral metabolism, is also a potent antiproliferative agent in a wide variety of malignant cell types. We have demonstrated that calcitriol has significant antitumor activity in vitro and in vivo in prostate and squamous cell carcinoma model systems. Calcitriol, in these models, induces a significant G0/G1 arrest and modulates p21(Waf1/Cip1) and p27(Kip1), the cyclin-dependent kinase inhibitors. Calcitriol induces poly (adenosine diphosphate-ribose) polymerase cleavage, increases bax/bcl-2 ratio, reduces levels of phosphorylated mitogen-activated protein kinases (P-MAPKs; also known as extracellular signal-related kinase [ERK] 1/2) and phosphorylated Akt, induces caspase-dependent mitogen-activated protein kinase kinase (MEK) cleavage and upregulation of MEK kinase-1, all potential markers of the apoptotic pathway. We also have demonstrated that dexamethasone (dex) potentiates the antitumor effect of calcitriol through effects on the vitamin D receptor and decreases calcitriol-induced hypercalcemia. We initiated phase 1 and phase 2 trials of calcitriol, either alone or in combination with carboplatin, paclitaxel, or dex. Data from these studies indicate that high-dose calcitriol is feasible on an intermittent schedule, the maximum tolerated dose (MTD) is unclear, and dex or paclitaxel appear to ameliorate hypercalcemia. Studies continue to define the MTD of calcitriol on this intermittent schedule, either alone or with other agents, and to evaluate the mechanisms of calcitriol effects in prostate cancer models.
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PMID:Vitamin D receptor: a potential target for intervention. 1223 Oct 68

Neoadjuvant/pre-surgical medical therapy of breast cancer provides a unique opportunity to derive biological information related to tumour response. Large clinical trials of neoadjuvant chemotherapy have established that pathological complete remission is an independent predictor of improved disease-free survival. Clinical response has been found to parallel substantial reductions in the proliferation of breast cancer cells. Increased apoptosis also occurs, but it is not closely associated with response. Numerous biological markers such as p53, bcl-2, oestrogen receptor (ER) and HER2 have been assessed for their possible role in chemoresistance/response, but the data are not clear at this stage. Continuing work using cDNA microarrays may yield new, more reliable indices of likely response and an improved insight into biological processes related to chemotherapeutic response.
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PMID:The biology of neoadjuvant chemotherapy for breast cancer. 1223 46

The biological behaviour of a gastrointestinal stromal tumor (GIST) cannot be easily predicted from preoperative clinical examination alone. As a result, there is little standardization in the surgical treatment of GIST. In this study, we analyzed the clinicopathology and immunohistochemistry of 20 cases of GIST to clarify factors associated with tumors showing malignant potential. Immunohistochemical analysis of KIT, CD34, vimentin, alpha-smooth muscle actin (SMA), s-100, p53, ki-67, bcl-2 and bax expression was performed on 20 surgically resected GIST. An apoptotic index (AI) was calculated for each sample using a TdT-mediated dUTP-biotin nick end-labeling method. With regard to bcl-2, t(14;18) translocations were also investigated using a polymerase chain reaction based method. Finally, the relationship between these biological results and clinicopathological data was analyzed. Of the 20 cases studied, two patients died due to lung or liver metastasis. All cases stained positive for vimentin, nine cases were positive for alpha-SMA and three cases positive for s-100. All cases were stained for both KIT and CD34, which tended to correlate with malignant potential. There was significant difference in frequency of bcl-2 overexpression (p<0.05) and trend in Ki-67 labeling index (p=0.098) between benign and malignant cases. However, with regard to bcl-2, no chromosomal t(14;18) translocations were detected in four analyzed cases. In GIST, overexpression of bcl-2 may play an important role in increasing malignant potential. Furthermore, Ki-67 L.I. and bcl-2 overexpression may be useful in predicting malignant potential, and therefore help to determine the surgical treatment, follow-up manner, and the necessity of adjuvant therapy.
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PMID:Biological analysis of gastrointestinal stromal tumors. 1237 34

In the current study we investigated the mechanism by which beta-estradiol-17-valerate (E2) induces apoptosis in T cells. To this end, C57BL/6 wild-type (+/+), Fas-deficient (C57BL/6-lpr/lpr), and FasL-deficient (C57BL/6-gld/gld) mice were treated with various concentrations of E2, including 75, 25, 5, 1, or 0.1 mg/kg body weight or the vehicle. The thymi from these mice were harvested on days 1, 4, or 7 following treatment, and cellularity and apoptosis were determined. Treatment with E2 caused a decrease in thymic cellularity at all doses except 0.1 mg/kg in all three groups of mice, particularly on days 4 and 7. Interestingly, however, the degree of thymic atrophy in C57BL/6-lpr/lpr and C57BL/6-gld/gld mice was significantly less than that seen in C57BL/6 wild-type mice. When thymocytes were analyzed for apoptosis, cells from C57BL/6-lpr/lpr and C57BL/6-gld/gld mice showed decreased levels of apoptosis. Moreover, cDNA array analysis of gene expression revealed that treatment with E2 upregulated several genes involved in apoptosis, including FasL, caspases, TRAIL, and iNOS, but not bcl-2 gene family. Reverse transcriptase-polymerase chain reaction data also demonstrated the increased expression of Fas and FasL genes following E2 treatment. Caspase 8 inhibitor blocked the E2-induced apoptosis of thymocytes in vitro. These data suggested that E2 may induce apoptosis by activating the death-receptor rather than the mitochondrial pathway. E2 treatment decreased the expansion of peripheral Vbeta3+ T cells to the bacterial superantigen SEA in vivo and their subsequent in vitro proliferative response to SEA, thereby suggesting increased induction of apoptosis in Vbeta3+ T cells. The current study suggests that E2 may trigger the death receptor pathway in vivo in T cells, thereby inducing apoptosis.
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PMID:Role of death receptor pathway in estradiol-induced T-cell apoptosis in vivo. 1238 36

Metastasized neuroendocrine tumors of the gastrointestinal tract and of unknown origin show a highly variable clinical course. Within this group, low-grade and high-grade malignant tumors can be recognized based on the revised classification of neuroendocrine tumors of the lung, pancreas, and gut published by Capella et al in 1995. The present study investigated whether fine-tuning the prediction of prognosis was possible by dividing the group of low-grade malignant tumors of the midgut and of unknown origin into typical and atypical carcinoids by grading them according to the World Health Organization (WHO) classification criteria for neuroendocrine tumors of the lung. Moreover, the prognostic value of immunohistochemical stainings and clinical parameters was evaluated. The study group comprised patients diagnosed between 1983 and 1999 with liver metastases of a neuroendocrine tumor of the midgut n = 40) or of unknown origin (n = 16). As a control for the consistency of grading, 10 patients with metastasized neuroendocrine tumors of the lung also were evaluated. Immunohistochemical stainings for chromogranin A, synaptophysin, Leu 7/CD57, neural cell adhesion molecule/CD56, cytokeratin 8, bcl-2, p53, ki67, and HER2/neu were performed. The clinical parameters age, gender, urinary 5-HIAA level, and presence or absence of the carcinoid syndrome were evaluated. Tumors of the midgut and of unknown origin were evaluated together, because they were clinically similar. In this group of 56 patients, both the Capella and the WHO classification systems recognized the high-grade malignant tumors with a bad prognosis. When the low-grade malignant tumors (Capella) were divided into typical and atypical carcinoids (WHO), no difference in survival was observed, but when the dichotomy into typical and atypical was based on mitotic count alone, the difference became borderline significant (P =.072). Of the immunohistochemical stainings used, synaptophysin, cytokeratin 8, and ki67 had limited prognostic value. Age above 60 was the only clinical parameter of unfavorable prognostic significance. We conclude that high-grade malignant neuroendocrine tumors of the midgut and of unknown origin are recognized by both the Capella classification and the WHO classification of neuroendocrine tumors of the lung. Further subdividing low-grade malignant tumors at this location appears to be of less value than in the lung, but assessing the mitotic activity of these tumors might be of prognostic value.
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PMID:Classification of low-grade neuroendocrine tumors of midgut and unknown origin. 1245 18

We report a rare case of solitary fibrous tumor of the parotid gland. A 47-year-old woman presented with a 3-year-history of left-sided subauricular swelling. Computed tomographic scans and magnetic resonance images revealed a well-defined and dumbbell-shaped mass, measuring about 30 mm in its greatest dimension, in the left parotid gland. Because the tumor occupied both superficial and deep lobes of the gland, she underwent total parotidectomy with preservation of the facial nerve. The microscopic finding showed short-spindle and ovoid cells arranged in a haphazard pattern with interspersed thin collagen fibrils. Immunohistochemically, the tumor cells were strongly positive for CD34, bcl-2 and vimentin, whereas stains for S-100, cytokeratin, smooth muscle actin, collagen type IV and CD117 (KIT) were negative. On the basis of these findings, the tumor was diagnosed as solitary fibrous tumor. Her post-operative course was uneventful, and she is currently free from disease 14 months after surgery. Diagnosis, clinical behavior and treatment of solitary fibrous tumor are reviewed from perusal of the literature.
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PMID:A case of solitary fibrous tumor of the parotid gland: review of the literatures. 1249 13

The optimal management of ductal carcinoma in situ (DCIS) is controversial, due in part to our poor understanding of its natural history. We undertook to identify subgroups of DCIS based on the expression of biomarkers, which were related to the likelihood of clinical recurrence. Biomarker expression of a total of 95 DCIS lesions in a nested case-control study within a population-based cohort with up to 135 months follow-up data (median 101 months) was analysed using immunohistochemistry. ERBB2-positivity and bcl-2-, oestrogen receptor (ER)- and progesterone receptor (PR)-negativity were individually associated with the risk of clinical recurrence. The predictive value of these biomarkers was independent of cytonuclear grade. ERBB2, bcl-2, ER and PR expression were conserved in the recurrent lesions, including subsequent invasive cancers. p21-positive DCIS was also associated with clinical recurrence, independently of the associations with ERBB2/bcl-2/ER/PR expression. These data identify clinically and biologically relevant subcategories of DCIS lesions, an essential basis for improving management.
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PMID:Biological markers that predict clinical recurrence in ductal carcinoma in situ of the breast. 1262 41


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