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)

A subclass of proteins with the SEA (sea urchin sperm protein, enterokinase, and agrin) domain fold exists as heterodimers generated by autoproteolytic cleavage within a characteristic G(-1)S+1VVV sequence. Autoproteolysis occurs by a nucleophilic attack of the serine hydroxyl on the vicinal glycine carbonyl followed by an N-->O acyl shift and hydrolysis of the resulting ester. The reaction has been suggested to be accelerated by the straining of the scissile peptide bond upon protein folding. In an accompanying article, we report the mechanism; in this article, we provide further key evidence and account for the energetics of coupled protein folding and autoproteolysis. Cleavage of the GPR116 domain and that of the MUC1 SEA domain occur with half-life (t((1/2))) values of 12 and 18 min, respectively, with lowering of the free energy of the activation barrier by approximately 10 kcal mol(-1) compared with uncatalyzed hydrolysis. The free energies of unfolding of the GPR116 and MUC1 SEA domains were measured to approximately 11 and approximately 15 kcal mol(-1), respectively, but approximately 7 kcal mol(-1) of conformational energy is partitioned as strain over the scissile peptide bond in the precursor to catalyze autoproteolysis by substrate destabilization. A straining energy of approximately 7 kcal mol(-1) was measured by using both a pre-equilibrium model to analyze stability and cleavage kinetics data obtained with the GPR116 SEA domain destabilized by core mutations or urea addition, as well as the difference in thermodynamic stabilities of the MUC1 SEA precursor mutant S1098A (with a G(-1)A+1VVV motif) and the wild-type protein. The results imply that cleavage by N-->O acyl shift alone would proceed with a t((1/2)) of approximately 2.3 years, which is too slow to be biochemically effective. A subsequent review of structural data on other self-cleaving proteins suggests that conformational strain of the scissile peptide bond may be a common mechanism of autoproteolysis.
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PMID:SEA domain autoproteolysis accelerated by conformational strain: energetic aspects. 1830 34

A subclass of SEA (sea urchin sperm protein, enterokinase, and agrin) domain proteins undergoes autoproteolysis between glycine and serine in a conserved G(-1)S+1VVV motif to generate stable heterodimers. Autoproteolysis has been suggested to involve only the intramolecular catalytic action of the conserved serine hydroxyl in combination with conformational strain of the glycine-serine peptide bond. We conducted a number of experiments and simulations on the SEA domain from the MUC1 mucin to test this mechanism. Alanine-scanning mutagenesis of polar residues in the vicinity of the cleavage site demonstrates that only the nucleophile at position +1 is required for efficient proteolysis. Molecular modeling shows that an uncleaved trans peptide is incompatible with the native heterodimeric structure, resulting in disruption of secondary structure elements and distortion of the scissile peptide bond. Insertion of glycine residues (to obtain G(n)G(-1)S+1VVV motifs) appears to relieve strain, and autoproteolysis is 100 times slower in a 1G (n=1) mutant and not measurable in 2G and 4G mutants. Removal of the catalytic serine hydroxyl hampers cleavage considerably, but measurable autoproteolysis of this S1098A mutant still proceeds in the presence of strain alone. The uncleaved SEA precursor populates interconverting partially folded conformations, and autoproteolysis coincides with adoption of proper beta-sheet secondary structure and completed folding. Molecular dynamics simulations of the precursor show that the serine hydroxyl and the preceding glycine carbonyl carbon can be in van der Waals contact at the same time as the scissile peptide bond becomes strained. These observations are all consistent with autoproteolysis accelerated by N-->O acyl shift and conformational strain imposed upon protein folding in a reaction for which the free-energy barrier is decreased by substrate destabilization rather than by transition-state stabilization. The energetics of this coupled folding and autoproteolysis mechanism is accounted for in an accompanying article.
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PMID:SEA domain autoproteolysis accelerated by conformational strain: mechanistic aspects. 1831 33

Krebs von den Lungen-6 (KL-6) is a high molecular weight glycoprotein classified in the category of human MUC1 mucin. KL-6 has been reported to serve as a sensitive marker for interstitial pneumonia; however, recent studies have suggested that it can also be used as a tumor marker as its origin shows. To further elucidate the clinicopathological significance of circulating KL-6 in lung cancer, we monitored the circulating KL-6 levels in advanced nonsmall cell lung cancer (NSCLC) patients and analyzed the association between these levels and the clinical outcome of EGFR-TKI treatment. The pretreatment levels of circulating KL-6 were found to be significantly higher in progressive disease (PD) patients than disease-controlled (partial response (PR) and stable disease (SD)) patients. Multivariate analyses revealed the circulating KL-6 level to be an independent prognostic factor for overall survival as well as progression-free survival. In addition to these observations, we found that changes in circulating KL-6 levels at 2 weeks after the start of EGFR-TKI treatment from the baseline could quite precisely discriminate PD cases from PR or SD patients and the clinical outcome of EGFR-TKI in NSCLC patients. These results indicate that the monitoring of circulating KL-6 levels in NSCLC patients is effective for both selecting patients to be treated with EGFR-TKI and predicting the clinical outcome of EGFR-TKI. In addition, the findings suggest that the circulating KL-6 level could be used as a clinically relevant biomarker in patients with NSCLC, particularly those who are candidates for EGFR-TKI treatment.
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PMID:Usefulness of monitoring the circulating Krebs von den Lungen-6 levels to predict the clinical outcome of patients with advanced nonsmall cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. 1832 27

The prognosis for patients with ovarian cancer is still poor and more effective therapeutic modalities are needed. (Radio)immunotherapy using monoclonal antibodies (Mabs) could be one of these approaches. Here, we review the status of (radio)immunotherapy using Mabs for the treatment of ovarian cancer. The Pubmed database was searched for clinical trials investigating the effect of (radio)immunotherapy in ovarian cancer published until October 1, 2007. Keywords for the search were: ovarian cancer, monoclonal antibodies, CA 125, gp38, HER2, HMFG, MUC1, TAG 72 and VEGF. A total of 44 trials on immunotherapy with unconjugated Mabs, Mab vaccination and (radio)immunotherapy directed towards the antigens CA 125, gp38, HER2, MUC1, TAG 72 or VEGF in patients with ovarian cancer were found, reviewed and discussed. Out of these trials, 23 studied immunotherapy with unconjugated Mabs, 5 vaccination with Mabs and 16 trials studied (radio)immunotherapy. The lack of large randomized prospective trials with Mabs directed to tumor-associated antigens expressed on ovarian cancer cells preclude any firm conclusion on the potential of Mabs use in the treatment of ovarian cancer. Oregovomab, directed against CA 125, and bevacizumab, targeting VEGF, are two unconjugated Mabs closest to clinical introduction for the treatment of ovarian cancer. Vaccination with Mab ACA 125 seems promising but these findings need to be confirmed in controlled randomized trials. Sole RIT should be investigated with the appropriate radionuclide and a Mab with high affinity for the specific tumor-associated antigen in the appropriate patient group to determine whether it may have a therapeutic effect. Additionally, appending (radio)immunotherapy with anti-TAG 72 or anti-MUC1 to other treatment strategies such as chemotherapy could also be a strategy worthwhile investigating. The potential of Mabs to complement current treatment paradigms, is encouraging and may bring a significant improvement to the overall therapeutic outcomes currently being achieved in ovarian cancer.
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PMID:The use of monoclonal antibodies for the treatment of epithelial ovarian cancer (review). 1849 76

We performed an integrated array comparative genomic hybridization (aCGH) and expression microarray analysis of 8 normal gastric tissues and 38 primary tumors, including 25 intestinal and 13 diffuse gastric adenocarcinomas to identify genes whose expression is deregulated in association with copy number alteration. Our aim was also to identify molecular genetic alterations that are specific to particular clinicopathological characteristics of gastric cancer. Distinct molecular genetic profiles were identified for intestinal and diffuse gastric cancers and for tumors obtained from 2 different locations of the stomach. Interestingly, the ERBB2 amplification and gains at 20q13.12-q13.33 almost exclusively discriminated intestinal cancers from the diffuse type. In addition, the 17q12-q25 gain was characteristic to cancers located in corpus and the 20q13.12-q13.13 gain was more common in the antrum. Statistical analysis was performed using integrated copy number and expression data to identify genes showing differential expression associated with a copy number alteration. Genes with the highest statistical significance included ERBB2, MUC1, GRB7, PPP1R1B and PPARBP with concomitant changes in copy number and expression. Immunohistochemical analysis of ERBB2 and MUC1 on a tissue microarray containing 78 independent gastric tissues showed statistically significant differences (p < 0.05 and <0.001) in immunopositivity in the intestinal (31 and 70%) and diffuse subtypes (14 and 41%), respectively. In conclusion, our results demonstrate that intestinal and diffuse type gastric cancers as well as cancers located in different sites of the stomach have distinct molecular profiles which may have clinical value.
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PMID:Integrated gene copy number and expression microarray analysis of gastric cancer highlights potential target genes. 1850 90

The pathogenesis of polycystic liver disease is not well understood. The putative function of the associated proteins, hepatocystin and Sec63p, do not give insight in their role in cystogenesis and their tissue-wide expression does not fit with the liver-specific phenotype of the disease. We designed this study with the specific aim to dissect whether pathways involved in polycystic kidney diseases are also implicated in polycystic liver disease. Therefore, we immunohistochemically stained cyst tissue specimen with antibodies directed against markers for apoptosis, proliferation, growth receptors, signaling and adhesion. We analyzed genotyped polycystic liver disease cyst tissue (n=21) compared with normal liver tissue (n=13). None of the cysts showed proliferation of epithelial cells. In addition, anti-apoptosis marker Bcl-2 revealed slight increase in expression, with variable increase of apoptosis marker active caspase 3. Growth factor receptors, EGFR and c-erbB-2, were overexpressed and mislocalized. We found EGFR staining in the nuclei of cyst epithelial cells regardless of mutational state of the patient. Further, in hepatocystin-mutant polycystic liver disease patients, apical membranous staining of c-erbB-2 and adhesion markers, MUC1 and CEA, was lost and the proteins appeared to be retained in cytoplasm of cyst epithelia. Finally, we found loss of adhesion molecules E-cadherin and Ep-CAM in cyst epithelium of all patients. Nevertheless, we observed normal beta-catenin expression. Our results show that polycystic liver disease cystogenesis is different from renal cystogenesis. Polycystic liver disease involves overexpression of growth factor receptors and loss of adhesion. In contrast, proliferation or deregulated apoptosis do not seem to be implicated. Moreover differential findings for PRKCSH- and SEC63-associated polycystic liver disease suggest a divergent mechanism for cystogenesis in these two groups.
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PMID:Disrupted cell adhesion but not proliferation mediates cyst formation in polycystic liver disease. 1858 25

Lymph node metastases are a major prognostic factor in cervical carcinomas. The aim of this study was to characterize the expression of 11 markers in cervical tumors and negative lymph nodes and to determine which ones could be helpful for improving the specificity of molecular diagnosis of nodal involvement. Using TaqMan RT-PCR, we studied the expression of CK19, MUC1, HER1-HER4, VEGF, VEGF-C, uPA, MMP9, and PRAD1 in uterine cervical tumors and in histologically nonmetastatic lymph nodes of 8 patients diagnosed with locally advanced cervical cancer. We observed that CK19, MUC1, HER1-HER3, uPA, and VEGF had a significantly higher expression in cervical tumors than in the negative nodes, whereas VEGF-C expression level was higher in the negative nodes than in the tumors. PRAD1 harbored similar expression levels in the tumors and in the negative nodes. Interestingly, 1 of the 4 patients who presented a clinical recurrence, showed elevated HER1, HER2, uPA, and VEGF in the histologically negative nodes. Our results suggest that CK19, MUC1, HER1-3, uPA, and VEGF are biomarkers that have a higher expression in tumoral cervical tissues compared with the negative lymph nodes and could be useful to diagnose nodal involvement in uterine cervical carcinoma. Our results should encourage us in continue to investigate a greater number of patients, including patients with histologically involved nodes.
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PMID:Measurement of mRNA of 11 biomarkers by RT-PCR to detect lymph node involvement in cervical cancer. 1862 79

Primary cutaneous anaplastic large-cell lymphoma (ALCL) ordinarily is distinguished from systemic ALCL by clinical presentation, absence of anaplastic lymphoma kinase (ALK) expression, and immunophenotype (CLA+, EMA/MUC1-). We present an exceptional case of an elderly man with primary cutaneous ALCL and no systemic disease for a 13-year period. Recurrent skin tumors in this patient were characterized by anaplastic, often multinucleated, cells infiltrating the lymphatics and associated with pseudoepitheliomatous hyperplasia. Cutaneous lymphocyte antigen was absent and EMA/MUC1, typical of systemic ALCL, was strongly expressed by the tumor cells. Remarkably, the tumor cells expressed a cytoplasmic-only variant of ALK protein, as reported in 3 previous cases of primary cutaneous ALCL. Fluorescence in situ hybridization revealed lack of rearrangements of the chromosome 2 ALK gene locus usually involved by translocation t(2;5) or other chromosomal rearrangements that generate nucleophosmin-ALK or the variant ALK fusions that occur in systemic ALCL. Nonetheless, the cytoplasmic ALK protein in the patient's tumor cells was shown to be phosphorylated/activated, suggesting a novel mechanism of ALK activation. Primary cutaneous ALCL of this novel subtype should be distinguished from systemic ALCL to ensure proper clinical management.
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PMID:Primary cutaneous ALCL with phosphorylated/activated cytoplasmic ALK and novel phenotype: EMA/MUC1+, cutaneous lymphocyte antigen negative. 1867 Mar 45

MUC1, a transmembrane glycoprotein, is abnormally over-expressed in most human adenocarcinomas. MUC1 association with cytoplasmic cell signal regulators and nuclear accumulation are important for its tumor related activities. Little is known about how MUC1 translocates from the cell membrane to the cytoplasm. In this study, live cell imaging was used to study MUC1 intracellular trafficking. The interaction between EGFR and MUC1 was mapped by FRET analysis and EGF stimulated MUC1 endocytosis was observed directly through live cell imaging. MUC1-CT endocytosis was clathrin and dynamin dependent. Rab5 over-expression resulted in decreased cell membrane localization of MUC1, with accumulation of MUC1 endocytic vesicles in the peri-nuclear region. Conversely, over-expression of a Rab5 dominant negative mutant (S34N) resulted in redistribution of MUC1 from the peri-nuclear region to the cytoplasm. Collectively, these results indicated that MUC1 intra-cellular trafficking occurs through a regulated process that was stimulated by direct EGFR and MUC1 interaction, mediated by clathrin coated pits that were dynamin dependent and regulated by Rab5.
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PMID:MUC1 intra-cellular trafficking is clathrin, dynamin, and rab5 dependent. 1881 66

Nowadays, biological cancer treatments represent the major advance in non-small cell lung cancer therapeutic strategies. During the last decade, more than 15 randomized trials associating chemo with biological treatments, in first line setting, have included more than 12,073 NSCLC patients, and as much in phase 2-3 trials in second and third line setting. Very few were positive, but currently anti-angiogenic strategy using the humanized monoclonal antibody bevacizumab has been approved in association with chemotherapy, in first line treatment of carefully selected NSCLC patients (with non proximal tumors, without cerebral metastasis, and of non-squamous histology). On the same way, monotherapy by the EGFR tyrosine kinase inhibitor erlotinib has been approved in second and third line setting, with comparable results as chemotherapy. 2008 was the year of new targeted therapies with cetuximab, the chimeric monoclonal antibody directed against EFGR, in association with chemotherapy in first line setting, whereas EGFR TKI are also tested in first line, in patients selected on the ground of the molecular properties of their tumors (with EGFR mutation or positive EGFR FISH). New generation EGFR TKI (more potent if not more selective) are developed in new settings (neo-adjuvant or adjuvant treatment), with promising results in phase 2 trials, whereas active immunotherapy directed toward MUC1 or MAGE-A3 are tested in large phase 3 randomized trials in adjuvant setting (post-surgery or post-radiotherapy), since phase 2 results were appealing. Therefore, during the last few years, targeted therapies quit science-fiction to enter in our current practice, leading clinicians to learn how to treat new kinds of toxicities and to select patients on molecular grounds.
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PMID:[Stage IV NSCLC. Biological treatments of lung cancer in 2008... and in the near future]. 1897 36


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