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)

Substantial progress in functional genomic and proteomic technologies has opened new perspectives in biomedical research. The sequence of the human genome has been mostly determined and opened new visions on its complexity and regulation. New technologies, like RNAi and protein arrays, allow gathering knowledge beyond single gene analysis. Increasingly, biological processes are studied with systems biological approaches, where qualitative and quantitative data of the components are utilized to model the respective processes, to predict effects of perturbations, and to then refine these models after experimental testing. Here, we describe the potential of applying functional genomics and proteomics, taking the ERBB family of growth-factor receptors as an example to study the signaling network and its impact on cancer.
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PMID:Functional genomics and proteomics approaches to study the ERBB network in cancer. 1930 77

The aim of the present study was the search of molecular alterations (oncogene amplification or protein overexpression) that could have an impact on the outcome of ACC patients. For this purpose, paraffin-embedded tissue samples of primary ACC of 24 patients were collected. Oncogenic amplification status of six targets previously described to be involved in human carcinogenesis (ERBB1, KIT, PIK3CA, CCND1, MYC and MDM2) were studied by a PCR-based semiquantitative approach. C-Kit, cyclin D1 and EGFR protein levels were immunohistochemically assessed. ERBB1, CCND1 and PIK3CA were frequent targets of oncogene amplification (67, 46 and 38%, respectively). C-Kit and cyclin D1 were overexpressed in 57 and 82%, respectively. CCND1 amplification was associated with advanced tumour stage and ERBB1 amplification to distant metastasis. ERBB1/CCND1/PIK3CA coamplification was the most consistently observed pattern (29%). The cases with this amplification pattern presented a reduced survival. This study points to the importance of ERBB1, CCND1 and PIK3CA oncogenic amplification status in ACC carcinogenesis.
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PMID:Oncogene amplification pattern in adenoid cystic carcinoma of the salivary glands. 1936 Feb 97

Signal transduction pathways regulated by the EGFR/ERBB/HER proto-oncogene family and receptor tyrosine kinases encoded by these genes are known to become dysregulated during cellular transformation and carcinogenesis. Consequently, biologically targeted antibodies and tyrosine kinase inhibitors directed toward EGFR/ErbB1/HER1 (eg, cetuximab, erlotinib and gefitinib) and ErbB2/HER2 (eg, trastuzumab), and more recently toward ErbB3/HER3 and ErbB4/HER4, are being investigated as therapeutic agents for treating patients with EGFR/ERBB/HER proto-oncogene-driven malignancies. The accurate selection of patients who will respond efficaciously to these agents a priori is a medical challenge. Understanding the clinical utility of soluble EGFR/ErbB/HER (ie, sEGFR/sErbB/sHER) isoforms, which are present in circulatory fluids, as theragnostic cancer biomarkers is an emerging area of contemporary biomedical investigation. This feature article reviews the literature regarding the clinical utility of serum sEGFR/sErbB1/sHER1 in breast, lung and ovarian cancer, and discusses the potential role of sEGFR in predicting and monitoring therapeutic responsiveness, as well as disease recurrence, and/or predicting disease outcome in patients treated with specific small-molecule, hormonal or biotherapeutic drug regimens. Well-designed translational research studies are needed to validate sEGFR as a theragnostic biomarker further and to achieve routine clinical implementation.
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PMID:Clinical implementation of soluble EGFR (sEGFR) as a theragnostic serum biomarker of breast, lung and ovarian cancer. 1943 Oct 95

Epidermal growth factor receptor (EGFR) is a member of the ERBB family of receptor tyrosine kinases that has been shown to play an important developmental and physiologic role in many aspects of pregnancy. We have previously shown in mice that Egfr(tm1Mag) nullizygous placentas have fewer proliferative trophoblasts than wild-type and exhibit strain-specific defects in the spongiotrophoblast and labyrinth layers. In this study we used mice with the hypermorphic Egfr(Dsk5) allele to study the effects of increased levels of EGFR signaling on placental development. On three genetic backgrounds, heterozygosity for Egfr(Dsk5) resulted in larger placental size with a more prominent spongiotrophoblast layer and increased expression of glycogen cell-specific genes. The C3HeB/FeJ strain showed additional placental enlargement of Egfr(Dsk5) homozygotes with a significant number of homozygous embryos dying prior to 15.5 days post-coitus (dpc). We also observed strain-specific subfertility in Egfr(Dsk5) heterozygous females and pregnancy loss was dependent on maternal factors rather than embryo genotype. Higher levels of phospho-EGFR were detected in the uterus of Egfr(Dsk5) heterozygotes but the structure of Egfr(Dsk5) heterozygous nonpregnant uteri appeared similar to wild-type. Collectively, our results demonstrate that mice with increased levels of EGFR signaling exhibit an extensive level of genetic background-dependent phenotypic variability. In addition, EGFR promotes growth of the placental spongiotrophoblast layer in mice, and EGFR expressed in the uterine stroma may play an underappreciated role in preparation of the uterus for embryo implantation.
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PMID:Placental overgrowth and fertility defects in mice with a hypermorphic allele of epidermal growth factor receptor. 1946 82

Cervical displasia are classified as CIN-I, CIN-II and CIN-III. It has been observed that in at least 60% of CIN-I and CIN-II, the pathology disappears spontaneously, while around 30% persist at 24 months, 10% progress to CIN-III and 1% develops as a SCC. The factors involved in the evolution of the pathology are not defined, although infection of HPV is a necessary condition, but not the only one. For this reason, the identification of genetic changes is an essential element for understanding the carcinogenic process. It can also serve as a helpful tool for identifying patients who may be susceptible to its evolution and treatment, from patients whose lesions could regress spontaneous and for whom periodic follow-ups would be enough. Fifty three cervical biopsies from patients with dysplasia and ISCC were included in the study. These biopsies were set into nine macroarrays. Eight genes and five proteins were examined in each samples (hTERT, PIK3CA, hTERC, MYC, CCND1, BCL2, ZNF217 and p16) by fluorescence in situ hybridization (FISH) and/or immunohistochemistry (IHC). The results reflected that the genetic alterations of PIK3CA, ZNF217 and CCND1 were associated with the evolution of normal tissue to CIN I, those of hTERC and ERBB with the evolution of LSIL to HSIL, those of hTERT and MYC with the evolution of CIN-II/CIN-III to ISCC, and those of BCL-2 with the inception of ISCC. With regards to proteins, the expression of MYC and CCND1 in the initial stages of the illness would help in the acquisition of the altered cellular phenotype.
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PMID:Analysis of gene status in cervical dysplastic lesions and squamous cell carcinoma using tissue microarrays. 1947 28

Pharmacologic blockade of EGFR or the closely related receptor ERBB2 has modest efficacy against colorectal cancers in the clinic. Although the upregulation of ERBB3, a pseudo-kinase member of the EGFR/ERBB family, is known to contribute to EGFR inhibitor resistance in other cancers, its functions in normal and malignant intestinal epithelium have not been defined. We have shown here that the intestinal epithelium of mice with intestine-specific genetic ablation of Erbb3 exhibits no cytological abnormalities but does exhibit loss of expression of ERBB4 and sensitivity to intestinal damage. By contrast, intestine-specific Erbb3 ablation resulted in almost complete absence of intestinal tumors in the ApcMin mouse model of colon cancer. Unlike nontransformed epithelium lacking ERBB3, intestinal tumors lacking ERBB3 had reduced PI3K/AKT signaling, which led to attenuation of tumorigenesis via a tumor-specific increase in caspase-3-mediated apoptosis. Consistent with the mouse data, which suggest that ERBB3-ERBB4 heterodimers contribute to colon cancer survival, experimentally induced loss of ERBB3 in a KRAS mutant human colon cancer cell line was associated with loss of ERBB4 expression, and siRNA knockdown of either ERBB3 or ERBB4 resulted in elevated levels of apoptosis. These results indicate that the ERBB3 pseudo-kinase has essential roles in supporting intestinal tumorigenesis and suggest that ERBB3 may be a promising target for the treatment of colorectal cancers.
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PMID:Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium. 1969 Mar 88

Tyrosine phosphorylation is important in signaling pathways underlying tumorigenesis. We performed a mutational analysis of the protein tyrosine kinase (PTK) gene family in cutaneous metastatic melanoma. We identified 30 somatic mutations affecting the kinase domains of 19 PTKs and subsequently evaluated the entire coding regions of the genes encoding these 19 PTKs for somatic mutations in 79 melanoma samples. We found ERBB4 mutations in 19% of individuals with melanoma and found mutations in two other kinases (FLT1 and PTK2B) in 10% of individuals with melanomas. We examined seven missense mutations in the most commonly altered PTK gene, ERBB4, and found that they resulted in increased kinase activity and transformation ability. Melanoma cells expressing mutant ERBB4 had reduced cell growth after shRNA-mediated knockdown of ERBB4 or treatment with the ERBB inhibitor lapatinib. These studies could lead to personalized therapeutics specifically targeting the kinases that are mutationally altered in individual melanomas.
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PMID:Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. 2002 3

Neuregulin-1 (NRG1) is both a candidate oncogene and a candidate tumour suppressor gene. It not only encodes the heregulins and other mitogenic ligands for the ERBB family, but also causes apoptosis in NRG1-expressing cells. We found that most breast cancer cell lines had reduced or undetectable expression of NRG1. This included cell lines that had translocation breaks in the gene. Similarly, expression in cancers was generally comparable to or less than that in various normal breast samples. Many non-expressing cell lines had extensive methylation of the CpG island at the principal transcription start site at exon 2 of NRG1. Expression was reactivated by demethylation. Many tumours also showed methylation, whereas normal mammary epithelial fragments had none. Lower NRG1 expression correlated with higher methylation. Small interfering RNA (siRNA)-mediated depletion of NRG1 increased net proliferation in a normal breast cell line and a breast cancer cell line that expressed NRG1. The short arm of chromosome 8 is frequently lost in epithelial cancers, and NRG1 is the most centromeric gene that is always affected. NRG1 may therefore be the major tumour suppressor gene postulated to be on 8p: it is in the correct location, is antiproliferative and is silenced in many breast cancers.
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PMID:The NRG1 gene is frequently silenced by methylation in breast cancers and is a strong candidate for the 8p tumour suppressor gene. 1980 2

The resorption, formation and maintenance of bone are coordinated by the action of several hormones, growth factors and transcription factors. Recent experiments based on genetically modified mouse models, gene microarrays and pharmacological intervention indicate that the epidermal growth factor receptor (EGFR) system plays important roles in skeletal biology and pathology. This network, including a family of seven growth factors - the EGFR ligands - and the related tyrosine kinase receptors EGFR (ERBB1), ERBB2, ERBB3 and ERBB4, regulates aspects such as proliferation and differentiation of osteoblasts, chondrocytes and osteoclasts, parathyroid hormone-mediated bone formation and cancer metastases in bone. Here, we summarize and discuss the role of the EGFR and its ligands in skeletal biology and pathology.
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PMID:The EGFR network in bone biology and pathology. 1981 18

Prior studies demonstrated that resistance to the ERBB1/2 inhibitor Lapatinib in HCT116 cells was mediated by increased MCL-1 expression. We examined whether inhibition of BCL-2 family function could restore Lapatinib toxicity in Lapatinib adapted tumor cells and enhance Lapatinib toxicity in naive cells. The BCL-2 family antagonist Obatoclax (GX15-070), that inhibits BCL-2/BCL-X(L)/MCL-1 function, enhanced Lapatinib toxicity in parental HCT116 and Lapatinib adapted HCT116 cells. In breast cancer lines, regardless of elevated ERBB1/2 expression, GX15-070 enhanced Lapatinib toxicity within 3-12 h. The promotion of Lapatinib toxicity neither correlated with cleavage of caspase 3 nor was blocked by inhibition caspases; and was not associated with changes in the activities of ERK1/2, JNK1/2 or p38 MAPK but with reduced AKT, mTOR and S6K1 phosphorylation. The promotion of Lapatinib toxicity by GX15-070 correlated with increased cytosolic levels of apoptosis inducing factor (AIF) and expression of ATG8 (LC3), and the formation of large vesicles that intensely stained for a transfected LC3-GFP construct. Knock down of the autophagy regulatory proteins ATG5 or Beclin1 suppressed the induction of LC3-GFP vesicularization and significantly reduced cell killing, whereas knock down of MCL-1 and BCL-X(L) enhanced the induction of LC3-GFP vesicularization and significantly enhanced cell killing. Knockdown of Beclin1 and AIF abolished cell killing. Collectively, our data demonstrate that Obatoclax mediated inhibition of MCL-1 rapidly enhances Lapatinib toxicity in tumor cells via a toxic form of autophagy and via AIF release from the mitochondrion.
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PMID:Inhibition of MCL-1 enhances lapatinib toxicity and overcomes lapatinib resistance via BAK-dependent autophagy. 1990 22


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