Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transmembrane domain of growth factor receptors, such as the epidermal growth factor receptor (EGFR) and the related c-erbB-2/neu oncogene protein, has been implicated in the process of receptor dimerization and mitogenic signal transduction, and hence in cellular transformation and oncogenesis. Amino acid substitutions in the transmembrane domain of the c-erbB-2/neu protein that cause a transforming effect may exert this effect through a conformational change from a bend conformation to an alpha-helical structure in this region of the protein, but similar amino acid substitutions at homologous positions in the transmembrane domain of the EGFR (e.g., Val-->Glu at position 627) fail to have a transforming effect. To examine whether this failure may be due to structural effects, we have used conformational energy analysis to determine the preferred three-dimensional structures for the nonapeptide sequence of the transmembrane domain of the EGFR from residues 623-631 with Val or Glu at position 627. The global minimum energy conformations of both nonapeptides were found to be non-alpha-helical with bends at positions 624-625 and 627-628. The failure of the Val-->Glu substitution to produce a conformational change to an alpha-helix in this region may be responsible for its lack of transforming effect. However, the presence of higher energy alpha-helical conformations for the nonapeptide from the normal EGFR may provide an explanation for the presence of a transforming effect from overexpression of the EGFR.
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PMID:Conformation of the transmembrane domain of the epidermal growth factor receptor. 791 27

Amplification of the Neu/c-erbB-2 receptor tyrosine kinase has been implicated as an important event in the genesis of human breast cancer. Indeed, transgenic mice bearing either an activated form of neu or the wild-type proto-oncogene under the transcriptional control of the mouse mammary tumor virus promoter-enhancer frequently develop mammary carcinomas (L. Bouchard, L. Lamarre, P. J. Tremblay, and P. Jolicoeur, Cell 57:931-936, 1989; C. T. Guy, M. A. Webster, M. Schaller, T. J. Parson, R. D. Cardiff, and W. J. Muller, Proc. Natl. Acad. Sci. USA 89:10578-10582, 1992; W. J. Muller, E. Sinn, R. Wallace, P. K. Pattengale, and P. Leder, Cell 54:105-115, 1988). Induction of mammary tumors in transgenic mice expressing the wild-type Neu receptor is associated with activation of the receptor's intrinsic tyrosine kinase activity (Guy et al., Proc. Natl. Acad. Sci. USA 89:10578-10582, 1992). Here, we demonstrate that activation of Neu in these transgenic mice occurs through somatic mutations located within the transgene itself. Sequence analyses of these mutations revealed that they contain in-frame deletions of 7 to 12 amino acids in the extracellular region proximal to the transmembrane domain. Introduction of these mutations into a wild-type neu cDNA results in an increased transforming ability of the altered Neu tyrosine kinase. These observations suggest that oncogenic activation of Neu in mammary tumorigenesis frequently occurs by somatic mutation.
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PMID:Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors. 793 22

Endometrial cancers have been considered to be less prevalent in Japan than in Western countries. However, with the increase in life expectancy, the Westernization of the Japanese diet, and changes in the hormonal environment, the prevalence of the disease has gradually increased even in our country. Similar increases in cancers of the breasts, lungs, colons, and ovaries have been noted in recent years. Much is still unknown regarding the pathogenesis and natural history of endometrial cancer. Although endometrial hyperplasia is considered to be a precancerous lesion of endometrial carcinoma, the relationship between those diseases has not been elucidated to the same degree as that between cervical cancer and cervical dysplasia, or carcinoma in situ. Research findings in genetic oncology have revealed that tumorigenesis involves a multi-step process. It is probable that activation of multiple genes, inactivation of anti-oncogenes, and disappearance of normal inhibitor genes occur in the process of the development of endometrial cancer. The purpose of this study is to elucidate the relationship between oncogenes and the development of endometrial cancer. In addition, the significance of endometrial hyperplasia as a clinical entity is also be evaluated. The roles played by oncogenes in endometrial cancers and endometrial hyperplasias were examined using the most recent molecular biological and immunohistochemical methods. Also, the differences in cellular proliferation and tissue invasiveness were discussed. Results obtained were as follows. Evaluation of cell proliferation (PCNA, FCM) revealed that there was no difference in proliferative activity between atypical hyperplasia and well differentiated adenocarcinoma. Evaluation of oncogene abnormalities (c-myc,c-erbB-2,K-ras,p53) revealed that the development of endometrial cancer was a multistep process involving several oncogenes, as it has been noted in the development of other cancers. Evaluation of extracellular matrix and related factors (cathepsin D, laminin, type IV collagen, tenascin, CD44) showed that tissue invasiveness differed between atypical hyperplasia and well differentiated adenocarcinoma.
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PMID:[Evaluation of the degree of biological behavior in endometrial hyperplasia and endometrial carcinoma: an investigation of proliferative activity, oncogene, and extracellular matrix]. 810 84

c-erbB-2 oncogene encodes a growth factor receptor whose amino acid sequence has extensive homology with human epidermal growth factor receptor. It is frequently overexpressed in human breast, ovary, lung, and stomach cancers, where its overexpression is related significantly to the prognosis. Tl investigate the possible role of c-erbB-2 oncogene in the oncogenesis of stomach cancer, we examined the genetic alterations of c-erbB-2 oncogene in 4 stomach cancer cell lines, SNU-1, SNU-5, SNU-16 and KATO III. There were no differences in c-erbB-2 mRNA level as well as c-erbB-2 gene copy number among them. But gp185-erbB-2, c-erbB-2 gene product, was increased from 2- to 4-fold in SNU-1 and SNU-5 cells, compared with that in SNU-16 or KATO III cells. Our results suggest that post-transcriptional regulation of gp185erbB-2 expression may underlie gp185erbB-2 overexpression in cancer cells.
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PMID:The mechanism of c-erbB-2 gene product increase in stomach cancer cell lines. 810 20

Acquired cystic disease of the kidney (ACDK) reveals abnormal epithelial cell growth which suggests a cotinuum of cyst, adenoma and renal cell carcinoma (RCC). In the present study, we examined potential role of vimentin and growth factors for cyst growth and proliferation in 20 cases with ACDK by immunoperoxidase staining method. 1281 cysts with single-layered epithelia and 89 cysts with multi-layered epithelia (atypical cyst) were studied. Intermediated filament, vimentin was positive in staining in 41.6% of cysts with single-layered epithelia, in 73.1% of cyst with multi-layered epithelia and in 100% of adenomas and RCCs. Vimentin expression, therefore, may be considered as an indication of cellular differentiation among proliferating tubular or intracystic cells. In order to evaluate the growth and/or proliferative capabilities of cyst epithelia, epidermal growth factor (EGF), epidermal growth factor receptor (EGFR) and c-erb B2 gene product were determined in cyst epithelia, adenoma and adenocarcinoma. EGF showed positive staining in 49.1% of cyst with single-layered epithelia, in 68.4% of cyst with multi-layered epithelia, in 2 of 3 adenomas and in 5 of 8 RCCs. EGFR expression was observed in 61.7% of cyst with single-layered epithelia, in 94.7% of cyst with multi-layered epithelia, in 100% of adenomas and RCCs. Co-expression of EGF and EGFR was observed in 40.3% of cyst with single-layered epithelia and in 67.1% of cyst with multi-layered epithelia. C-erb B2 gene product was positive in 9.7% of cyst with single-layered epithelia, in 100% of cyst with multi-layered epithelia and in 3 of 7 RCCs. These findings indicate that the expression of vimentin and overexpression of these growth factors and receptors appear to be one of the mechanisms operating in potentiating the abnormal growth of cyst epithelia, including potential for oncogenesis of RCC.
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PMID:[Immunohistochemical study in acquired cystic disease of the kidney--expression of vimentin, epidermal growth factor, epidermal growth factor receptor and c-erb B2 gene product]. 810 22

Phenotypic biochemical markers of oncogenesis and differentiation were mapped in bladder biopsies to investigate changes that occur in bladder tumorigenesis and to identify markers for increased bladder cancer risk. Touch preparations from biopsy specimens from 30 patients were obtained from tumors, the adjacent bladder epithelium, and random distant bladder epithelium. Markers, including DNA ploidy, epidermal growth factor receptor (EGFR), and oncoproteins, were quantified in individual cells by using quantitative fluorescence image analysis. Cluster analysis revealed the markers fell into three independent groups: (i) G-actin and EGFR; (ii) ploidy, cytology, and p185 (HER-2/neu oncoprotein) (ERBB2); and (iii) p300, a low-grade tumor antigen. Each marker displayed a gradient of abnormality from distant field to adjacent field to tumor. Different patterns for each marker suggested a developmental sequence of bladder cancer oncogenesis; G-actin was altered in 58% of distant biopsies (vs. 0/6 normals, P < 0.001), ploidy and cytology were altered in < 20% of distant fields and approximately 80% of tumors, and the other markers were intermediate. Patterns of EGFR and p185 suggest low-and high-grade tracks diverge early (P < 0.05 by Mann-Whitney U test for EGFR and ANOVA for p185). In conclusion, this study shows that a sequence of phenotypic changes accompanies development and progression of bladder cancers. Biochemical alterations in cells of the bladder field are often detectable before abnormal pathology, and markers previously thought to be limited to tumors were found in the field. The hierarchy of expression may be useful in identifying high-risk patients, assessing completeness of response to therapy, and monitoring and predicting recurrence.
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PMID:Alterations in phenotypic biochemical markers in bladder epithelium during tumorigenesis. 836 95

Initiation of oncogenesis in the immature peripheral nervous system (PNS) of rats by the DNA-reactive carcinogen N-ethyl-N-nitrosourea (EtNU) involves a specific T:A-->A:T transversion mutation at nucleotide 2012 of the neu (erbB-2) receptor tyrosine kinase gene in cells of the Schwann cell lineage. Although this mutation is invariably detected in the resulting malignant schwannomas, it is not found in EtNU-induced tumors of the central nervous system (CNS). We have evaluated expression of the neu gene in the PNS and CNS as a function of developmental stage. Cellular levels of neu mRNA and gp185neu were analyzed in the trigeminal and sciatic nerve and in brain, using a quantitative reverse transcription-polymerase chain reaction, in situ hybridization, immunocytochemistry, and fluorescence-activated cell sorting. In the PNS, expression of the neu gene is restricted to cells of the Schwann cell lineage and markedly exceeds expression in the CNS from prenatal day 20 onward. In trigeminal Schwann cells, neu mRNA is most abundant (2.8 x 10(7) copies/micrograms of RNA) on postnatal day 1, coincident with both the end of maximum mitotic activity and the "developmental window" of highest sensitivity to malignant transformation by EtNU. The subsequent decrease of neu gene expression is accompanied by decreasing proliferative activity and the onset of myelination. The level of neu gene expression may thus be critical to proliferation versus differentiation decisions in the Schwann cell lineage. EtNU-induced mutation of the neu gene in proliferative Schwann cell precursors expressing gp185neu may abrogate their responsiveness to extracellular and/or intrinsic controls, resulting in sustained proliferative activity and malignant conversion.
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PMID:Schwann cell lineage-specific neu (erbB-2) gene expression in the developing rat nervous system. 846 60

The RET proto-oncogene encodes a member of the receptor tyrosine kinase family. Multiple endocrine neoplasia type 2B (MEN 2B) is caused by the mutation of a conserved methionine to a threonine in the catalytic domain of the RET kinase. When the MEN 2B point mutation was introduced into the epidermal growth factor (EGF) receptor (M857T EGFR), the intrinsic tyrosine kinase activity of the mutant receptor was similar to that of wild-type EGF receptor and remained ligand-dependent. However, the mutant receptor showed an enhanced transforming capacity compared to the wild-type receptor as judged by its ability to mediate the growth of NIH 3T3 cells in soft agar. Using the oriented peptide library approach to examine substrate specificity, the M857T mutation was found to be associated with a decrease in the selectivity of the receptor for Phe and an increase in the selectivity for acidic residues at the P + 1 position as compared to wild-type EGF receptor. Short-term responses to EGF were similar in cells expressing wild-type and M857T EGF receptors. However, significant differences in receptor down-regulation were observed between the two receptors. These data demonstrate that the MEN 2B point mutation alters the substrate specificity of receptor tyrosine kinases and suggest that the enhanced oncogenesis associated with the MEN 2B mutation may be due in part to alterations in receptor regulation.
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PMID:The multiple endocrine neoplasia type 2B point mutation alters long-term regulation and enhances the transforming capacity of the epidermal growth factor receptor. 862 56

Mutational activation of the neu (erbB-2) receptor protein tyrosine kinase gene appears to be the triggering event in the process of oncogenesis induced by N-ethyl-N-nitrosourea (EtNU) in immature Schwann cells of the rat peripheral nervous system. Subsequent loss of the wild-type neu allele may represent a critical secondary step towards malignancy. Developmentally-regulated expression of a wild-type rat neu transgene (neu cDNA under the control of the rat Po promoter) in the Schwann cells of transgenic BDIX and Sprague-Dawley rats exposed to EtNU on postnatal day 1 results in a lower incidence of early atypical proliferates in the trigeminal nerve. Furthermore, re-introduction of the wild-type neu gene into homozygous neu mutant schwannoma cells counteracts the expression of the tumorigenic phenotype. The suppressive action of the wild-type gene over its mutationally activated oncogenic homologue underlines the critical function of the neu gene in the control of differentiation in the Schwann cell lineage, and provides evidence for the responsiveness of cellular phenotypes towards quantitative shifts in the dosage of wild-type vs mutant signal transducing molecules.
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PMID:Wild type neu transgene counteracts mutant homologue in malignant transformation of rat Schwann cells. 864 33

Fifty-one cases of esophageal squamous cell carcinoma were immunohistochemically investigated with monoclonal c-erbB 2 oncoprotein antibody. No tumor showed plasma membrane immunostaining for c-erbB-2 protein. Occasionally, unspecific cytoplasmic staining was found in minor tumor cell populations. The present results show that c-erbB-2 oncoprotein is not overexpressed in esophageal squamous cell carcinomas and does not play a central role in the tumorigenesis.
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PMID:Lack of expression of c-erbB-2 oncoprotein in human esophageal squamous cell carcinomas. 866 67


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