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At least 19 recordsLinked to original sources
PubMed1994

Amplification and differential expression of members of the erbB-gene family in human glioblastoma.

The objective of the present study was to determine the frequency of amplifications of three different members of the erbB gene family in human glioblastoma multiforme (GBM). We investigated 47 glial tumors (37 GBM WHO grade IV, 5 anaplastic astrocytomas WHO III and 5 astrocytomas WHO II) by Southern and Western analysis, and immunocytochemistry. Gene amplification of erbB genes in human malignant gliomas was restricted to the EGF receptor (EGFR) gene, erbB-1. We found amplification of the EGFR gene in 49% (18/37) of GBM but not in the astrocytomas WHO II/III. The erbB-2 and erbB-3 genes showed no amplification in the tumor specimens investigated in this study. At the protein level we found overexpression of the EGF receptor in 86% (32/37) by Western analysis and in 92% (34/37) by immunocytochemistry. Expression of the ERBB2 protein was present in 54% (20/37) but immunoreactivity was much weaker than for EGF receptor and in most cases barely detectable by Western analysis and immunocytochemistry. The ERBB3 protein was not expressed in the glial tumors investigated in this study. Of the three erbB genes only gene amplification and overexpression of the EGF receptor seems to have an impact on tumor progression of human gliomas. Our data from immunohistochemistry indicate that ERBB2 expression in GBM is closely correlated with EGF receptor levels and is therefore not useful as an independent prognostic parameter.

Adult↗
PubMed1995

Prognostic relevance of aberrations in the erbB oncogenes from breast, ovarian, oral and lung cancers: double-differential polymerase chain reaction (ddPCR) for clinical diagnosis.

We have determined the average gene copy numbers (AGCN) of the erbB-1 gene, encoding the epidermal growth factor receptor (EGF-R), the erbB-2 and the erbB-3 genes in breast, ovarian, oral, and lung cancer tissue by using double-differential PCR (ddPCR). The ddPCR method comprises the co-amplification of the single-copy gene HBB, the erbB-1, erbB-2 and erbB-3 oncogenes and the second single-copy reference gene SOD2 under equal reaction conditions. In a retrospective study the AGCN of the erbB genes and the time up to the appearance of metastases were subjected to life-table analysis in 128 women with primary breast cancer. Patients whose breast cancer tissue showed an AGCN for erbB-1 of less than 0.4 and greater then 1.6, as expected from the literature, for erbB-2 of greater than 2.0 and for erbB-3 of less than 1.75 had decreased disease-free survival (DFS). The quotient of erbB-1 and erbB-2 AGCN was the most significant in multivariate Cox analysis followed by nodal status and progesterone receptor status. In extensive studies a similar association between erbB AGCN and metastasis was seen in ovarian cancer and oral cancer, though erbB oncogene aberrations in those entities were not as frequent as in breast cancer. The AGCN of erbB oncogenes may not be of prognostic value in untreated lung cancer patients.

Base Sequence↗
PubMed1994

Detection and cloning of potent transforming gene(s) from chewing tobacco-related human oral carcinomas.

High molecular weight DNA isolated from 14 primary tumour tissues of human oral carcinoma patients was analysed for transforming activity by NIH3T3 co-transfection assay using pSV2neo gene as a selectable marker, followed by nude mouse tumorigenicity assay. Ten of the patient tumour tissues demonstrated molecular lesions in myc, ras or/and EGF-R genes, whereas 4 patients did not show tumour associated aberrations in these oncogenes. The G418-resistant transfected cells from 12 of 14 individual patients demonstrated transforming potential by colony formation in soft agar and tumour induction in nude mice within 25-80 days. DNAs from the transfected cells, consequent nude mice tumours and corresponding cell lines, contained human Alu sequences. Southern blot hybridisation with ras, myc, EGF-R oncogenes demonstrated the presence of human H-ras oncogene in one of the 12 sets of nude mice tumours. In contrast, DNA from the other 11 sets of nude mice tumours indicated absence of c-myc, N-myc, L-myc, H-ras, K-ras, N-ras and EGF-R genes on Southern analysis. Further, DNAs from five first cycle tumorigenic transformants were subjected to a second cycle of transfection, and induced tumours in nude mice with a shorter latency period of 21-50 days. The secondary transformants contained discrete human Alu sequences; however, the DNA did not hybridise with myc/ras/EGF-R probes. A genomic library was constructed from a second cycle nude mice tumour, using EMBL-3 as the vector. Four human Alu sequence positive clones were isolated on screening 2 x 10(5) plaques, and one of the recombinant clones subjected to fine restriction mapping using 16 restriction enzymes. The lack of association of the nude mice tumour DNA with myc/ras/EGF-R showing aberrations in the primary human tumour, implies activation of an alternative potent transforming gene(s) in the chewing tobacco-related oral carcinomas in India.

3T3 Cells↗
PubMed1989

Amplification of protooncogenes in surgical specimens of human lung carcinomas.

The possible existence of amplification or rearrangement of protooncogenes was examined in more than 100 surgical specimens of human lung carcinoma. Protooncogenes were amplified in 28% of the carcinomas. About 90% of the amplified genes were of the myc, ras, or erbB family. Of the myc family genes, myc was amplified in 14 of 137 tumors and L-myc in four of 108 tumors, but N-myc was not amplified. A high frequency of amplification of myc was observed in squamous cell carcinomas (seven of 37) and of L-myc in small cell carcinomas (two of six). Of the ras family genes, K-ras-2 was amplified in six of the 137 tumors and N-ras in two of the 137 tumors, but no amplification of H-ras-1 was detected. Seven of the eight cases of amplified ras genes were in advanced pathological stages. Of the erbB family genes, erbB-1 (epidermal growth factor receptor) was amplified in 10 of 114 tumors and erbB-2 (HER-2/neu) in one of 51 tumors. Amplifications of the myc, ras, and erbB family genes might be one of the crucial DNA abnormalities involved in the development of human lung carcinomas.

DNA, Neoplasm↗
PubMed1994

[Alterations of oncogenes in human fetal esophageal epithelium induced by N-methylbenzylnitrosamine (NMBzA)].

Epidemiological investigation showed that N-methylbenzylnitrosamine (NMBzA) has been associated with increased incidence of esophageal cancer (EC) in Linxian county, a high incidence area. In present study, our results indicate that NMBzA can induce amplification and over-expression of EGFr gene in human fetal esophageal epithelium (HFE) treated with NMBzA for 24 hours as shown by southern blot assay and immunohistochemistry. The papillary hyperplasia was induced in HFEs that cultured with NMBzA for 1 to 3 weeks. Amplification of c-myc and int-2 gene in HFEs treated by NMBzA for 1 week and 3 weeks was found, respectively. Deletions of p53 and Rb gene were found in human fetal esophageal carcinomas induced by NMBzA. Overexpression of p53 protein in human fetal esophageal carcinomas detected by immunohistochemical methods indicates that p53 gene mutation(s) may be occured. The HFE explants treated in vitro with NMBzA for 3 weeks were inoculated subcutanously into balb/c nude mice. No tumor was found in 5 months after inoculation, suggesting that only changes of oncogene(s) are insufficient to induce full transformation. Other genetic alterations (such as functional inactivation of Rb or/and p53 tumor suppressor genes) may be necessary in the further progression of malignant lesions.

Carcinogens↗
PubMed1994

[Regeneration of transplanted human liver: gene expression at the time of graft implantation].

The liver tissue mRNA expression of protooncogenes c-fos, c-myc, c-Ha-ras, c-met and c-erb B1, and TGF alpha and TGF beta genes is sequentially and temporarily increased in the early stages after partial hepatectomy, ischaemia or other mitogenic stimuli. These gene expressions were studied in 38 samples of liver tissue from 24 patients who underwent orthotopic liver transplantation, at different evolution stages. Eleven samples were obtained from surgical liver biopsies before graft implantation at day 0 (Group A), 14 samples from percutaneous liver biopsies during the post-operative period from day 9 to day 48 (Group B) and 13 samples in the long-term follow-up period from day 102 to day 1,382 (Group C). Gene expression was studied using 32P-labeled cDNA and oligonucleotidic probe hybridization in slot blots. A GAPD gene was used as a control gene. All expression values of protooncogenes were related to those of the GAPD gene. After cold ischaema, the relative gene expression (quantity of specific mRNA/quantity of GAPD mRNA ratio) tended to diminish in most cases. The relative expressions of c-fos, c-myc, c-Ha-ras, c-met and TGF alpha gene were correlated at day 0. During and after the liver transplantation, an overexpression of c-fos, c-myc, c-Ha-ras, c-met and TGF alpha was observed in different pathological conditions such as cold ischaemia and conservation injury, acute rejection, and cytomegalovirus infection. In three cases the relative expression values of c-fos, c-myc and c-Ha-ras increased over long-term follow-up without any associated acute pathology. These results suggest the necessity of an intercellular mediation--by means of graft reperfusion--in induction of hepatocyte proliferation and regeneration of the transplanted liver.

Adult↗
PubMed1991

Expression during Drosophila development of DER, a gene related to erbB-1 and neu: correlations with mutant phenotypes.

We used in situ hybridization to study expression of the DER gene during Drosophila development. DER encodes a transmembrane cell-surface receptor with a cytoplasmic protein-tyrosine kinase domain, and resembles the vertebrate genes that encode the EGF receptor and the neu protein. We examined most stages of development in the Drosophila life cycle and found a substantial correlation between DER expression and the phenotypes associated with a variety of mutant alleles. Of particular note were high levels of expression in the primordia of the mouth parts, which are the embryonic tissues most sensitive to reductions in DER activity; discrete expression in a subset of neural cells essential for construction of the axonal scaffold, a structure that is deformed in mutant embryos; uneven expression in the eye disc, the development of which is abnormal in both mild hypomorphs and hypermorphs; and expression in the follicular epithelial cells of the ovary, which are responsible for producing the eggshell of developing oocytes and do so aberrantly in the mildest hypomorphs. However, DER transcripts were also detected in a subset of tissues that have not been reported to be abnormal in mutant organisms. Our findings agree with and extend recently reported results for the DER protein, indicating that DER is regulated primarily at the level of transcription, in contrast to previous suggestions. We conclude that the phenotypes displayed by recessive mutants can be attributed to loss of DER function in the affected tissues.

Animals↗
PubMed1995

Gene amplification in human gliomas.

Gliomas represent the largest group of primary brain tumors in adults. The astrocytic variants are the most common and the adult forms are histologically stratified into three malignancy grades. Of these glioblastoma is the most common and the most malignant; it has also been best studied by molecular genetics and cytogenetics. Double-minute chromosomes, known to represent amplified genes, are found in 50% of glioblastomas. Amplified genes are not detected in the most benign of the astrocytomas. Many genes have been shown to be amplified in more than single cases of gliomas and these include EGFR, CDK4, SAS, MDM2, GLI, PDGFAR, MYC, N MYC, MYCL1, MET, GADD153, and KIT. The most commonly amplified genes in glioblastomas are EGFR (in approximately 40%), CDK4, and SAS (in approximately 15%). The remainder of the genes are amplified at lower frequency. The best mapped amplicon in gliomas involves the 12q13-14 region. The amplicon is of undetermined size, encompasses a number of genes, and may be rearranged. It occurs in 15% of glioblastomas and almost always includes the CDK4 and SAS genes, in about 10% of tumors the MDM2 gene, and at lower frequency GLI, GADD153, and A2MR. All but A2MR are overexpressed if amplified. The amplified EGFR gene is frequently rearranged, resulting in changes in the regions of the transcript that codes for the extracellular domain. The resultant receptor is constitutively activated. These findings provide examples of the impact the use of modern molecular biological techniques has had on our understanding of oncogenic mechanisms in gliomas.

Adult↗
PubMed1994

Triplex-forming oligonucleotide binding represses transcription of the human c-erbB gene in glioma.

Mixed purine-pyrimidine oligodeoxynucleotides were designed to form collinear DNA triplexes with pyrimidine-rich elements in the EGFR gene promoter. Their effects as mediators of human epidermal growth factor receptor (EGFR) gene transcription and subsequent gene expression were evaluated using human squamous cell carcinoma (A431) and human glioma cell line (U251MG and U87MG). Gel shift analysis indicated that the oligonucleotide forms a collinear triplex within the duplex Sp-1 binding site. An in vitro assay system revealed a correlation between triplex formation and the repression of EGFR transcription. We postulate that guanine residues are not always optimum in apposition to G-C pairs to form triple helices in the target. Site-specific oligodeoxynucleotides binding to a DNA duplex may serve as the basis for an alternative program of gene control in vitro.

Base Sequence↗
PubMed1995

Transformation of erythroid progenitors by viral and cellular tyrosine kinases.

Recently, two different normal avian erythroid progenitors were described. They differ in the receptor tyrosine kinases they express and in their ability to undergo self-renewal in culture. A common progenitor, termed stem cell factor (SCF) progenitor, expresses the receptor for avian SCF c-Kit, and undergoes short-term self-renewal when grown in the presence of avian SCF. A second progenitor, referred to as SCF/transforming growth factor-alpha progenitor, coexpresses c-Kit and the avian epidermal growth factor receptor homologue c-ErbB. These progenitors undergo sustained self-renewal when grown in the presence of transforming growth factor-alpha plus estradiol. The phenotype of the normal SCF/transforming growth factor-alpha progenitors closely corresponded to that of erythroid cells transformed by the tyrosine kinase oncogenes v-erbB or v-sea. This suggested that these cells, but not the SCF progenitors, would be the target cells for erythroblast transformation by these oncogenes. However, we demonstrate that both progenitor cells can be transformed by the v-erbB and v-sea oncogenes and also by the ligand-activated proto-oncogene product c-ErbB. We conclude that the target cell specificity of certain tyrosine kinase oncoproteins for erythroid cells is a reflection of their ability to provide signals for self-renewal that normally emanate from the endogenous c-ErbB protein.

Animals↗
PubMed1996

Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns distinct from those stimulated by epidermal growth factor or neuregulin-beta.

Betacellulin is a member of the epidermal growth factor (EGF) family. These soluble proteins are ligands for one or more of the four receptor tyrosine kinases encoded by the erbB gene family (erbB-1/epidermal growth factor receptor (EGFR), neu/erbB-2/HER2, erbB-3/HER3 and erbB-4/HER4). While evidence suggests that betacellulin is a ligand for the EGFR, the ability of betacellulin to regulate other erbB family receptors has not been analysed. Previously we engineered derivatives of the mouse Ba/F3 hematopoietic cell line to ectopically express erbB family receptors, singly and in pairwise combinations. We have stimulated this panel of cell lines with betacellulin and two other EGF family members, EGF itself and neuregulin-beta (NRG-beta). In the cell lines expressing a single erbB family receptor, betacellulin not only stimulated EGFR tyrosine phosphorylation, but it activated erbB-4 as well. Furthermore, in the double recombinant Ba/F3 derivatives, betacellulin stimulated a complex pattern of receptor phosphorylation distinct from the patterns activated by NRG-beta and EGF. Moreover, betacellulin stimulated a complex pattern of interleukin-3 independence in the Ba/F3 derivatives distinct from those activated by NRG-beta and EGF. These data identify a novel receptor for betacellulin and establish that different EGF family ligands activate distinct patterns of receptor phosphorylation and coupling to cellular signaling pathways.

Amino Acid Sequence↗
PubMed1995

Double-differential PCR for gene dosage estimation of erbB oncogenes in benign and cancer tissues and comparison to cellular DNA content.

Competitive and differential quantitative PCR methods circumvent the limiting factors of PCR which cause poor reproducibility. We describe the development and performance evaluation of another quantitative PCR method, double-differential PCR (ddPCR). The ddPCR method comprises the co-amplification of the single-copy gene HBB, the erbB-1, erbB-2 and erbB-3 oncogenes and the second single-copy reference gene SOD2 under equal reaction conditions. The ratio of band intensities of the PCR products in silver-stained polyacrylamide gels expresses the average gene copy number (AGCN) per cell of the erbB oncogenes. The coefficient of variability (CV) was less than 25% for an AGCN of 1. The PCR data were in correlation to the results from dot blotting. DNA image analysis did not reveal any correlation between DNA content and gene dosage deviation of the erbB oncogenes. The method was applied to normal breast tissue, benign breast diseases, breast cancer tissue and lymph node metastases. We suggest this method as being reproducible, low cost and rapid, and therefore suitable for clinical studies on erbB oncogene dosage estimation.

Base Sequence↗
PubMed1986

Nakahara memorial lecture. Non-receptor type protein-tyrosine kinases closely related to src and yes compose a multigene family.

We have determined the total coding sequence of human c-yes, a non-receptor type protein-tyrosine kinase gene, and found that the c-yes gene closely resembles the c-src gene. Recently, two new genes, syn and lyn, were found to encode proteins closely related to the yes product. In addition, we also determined the partial sequence of fgr. These genes together with lck reported by two American groups have very closely related structures and are thought to compose a closely related group of non-receptor type protein-tyrosine kinases. Partial analysis of the structures of these genes indicated that they have identical splicing junctions at all sites so far examined. On the other hand, the erbB-1/EGF (epidermal growth factor) receptor gene and the erbB-2/neu gene have completely different splicing junctions from those of the above gene group even in the kinase domain, although these genes also have protein kinase activity specific for tyrosine residues and the erbB-1 and -2 genes share splicing sites. These results suggest that the genes of the group of six non-receptor type kinases and those of the erbB-1 and erbB-2 gene group are descendants evolved by duplication of two distinct ancestor genes and are members of two distinct multi-gene families. The genes coding for protein kinases may be members of a super-family including multiple distinct gene families.

Amino Acid Sequence↗
PubMed1989

Cytokines and oncogene activity.

Cytokines play a part in the control of cellular growth, differentiation and development. Given such pleiotropic activities, it is not unexpected that the expression of the cytokines is tightly regulated. When cytokine-mediated processes are altered by mutation and/or overexpression of some cytokine or cytokine receptor genes, oncogenic transformation can occur. Oncogenes which derive their transforming potential through this mechanism include sis, which represents the activated form of the platelet-derived growth factor B chain, hst1/K-fgflint-2, which share appreciable homology with the gene family of fibroblast growth factors, fms, which is related to the cell surface receptor for macrophage-colony stimulating factor, and erbB-1, which encodes a truncated form of the epidermal growth factor receptor. Cytokine treatment has resulted in modulation of aberrant oncogene activity in some model systems.

Animals↗
PubMed1995

Targeted inhibition of tumor-cell growth by recombinant heregulin-toxin fusion proteins.

Fusion of functional domains of proteins by in vitro recombination of gene fragments can be used to generate novel anti-tumor agents. The combination of tumor-cell-recognition functions and toxic functions results in cytotoxic molecules with a high specificity for tumor cells. Human adenocarcinomas are frequently characterized by over-expression of members of the epidermal-growth-factor (EGF) receptor family (ErbB-1, 2, 3 and 4), when compared with normal cells. These tumors are particularly suited to treatment with recombinant toxins. The human heregulins (HRG) and their rat counterparts (neu differentiation factor, NDF) have been identified as ligands for these receptors. Two chimeric heregulin-toxin fusions consisting of the EGF-like receptor recognition domain of the heregulin isoforms HRG alpha and HRG beta I, and the domains II, Ib and III of the Pseudomonas exotoxin A (ETA) were constructed. HRG beta I-ETA is highly cytotoxic for the mammary carcinoma cell lines SK-BR-3 and MDA-MB-453. HRG alpha-ETA was less active than HRG beta I-ETA. The killing activity of the recombinant toxins correlated with the expression levels of ErbB-3 and/or ErbB-4 in the cell lines studied. High expression of ErbB-2 is not sufficient to confer sensitivity towards the HRG-ETA. Treatment of mice with 0.4 mg/kg/day of HRG beta I-ETA caused growth retardation of transplanted human breast tumor cells. Higher levels of HRG beta I-ETA administration resulted in acute hemorrhagic necrosis of the liver.

ADP Ribose Transferases↗
PubMedDate not supplied

[Complex characteristics of the alterations of oncogenes HER-2/ERBB-2, HER-1/ERBB-1, HRAS-1, C-MYC and antioncogenes p53, RB1, as well as deletions of loci of chromosome 17 in colon carcinoma].

Abnormalities of some oncogenes, antioncogenes and losses of heterozygosity (LOH) of chromosome 11p, 17p, and 17q in colorectal carcinomas (CC) was studied. Amplification of ERBB-1/HER-1 oncogene was detected in 2 of 56 cases; ERBB-2/HER-2- in 4 of 62. There was a lack of evidence for C-MYC oncogene amplification (67 cases). LOH of chromosome 11p (HRAS-1 probe) was found in 2 of 37 informative (heterozygous) cases; such events were not accompanied by point mutations in "hot" codons (12th or 61st) in the remaining allele. Prevalence of A3 and A4 alleles of HRAS-1 oncogene (68 cases) as compared to healthy donors was noted. RB-1 (41 cases) and p53 (62 cases) suppressor genes did not show any alterations in Southern-blot analysis. LOH of chromosome 17p (YNZ-22 probe) was found in 15 of 26 heterozygous CC; 17q (THH-59 probe)--in 4 of 16. Analysis of 175th codon of p53 gene revealed only one case of mutation in 35 CC studied. Finally, we were able to detect genetic alterations in 23 of 40 (58%) CC, that were studied on each parameter using Southern-blot. We failed to find any correlation between various molecular abnormalities or clinical characteristics. The data obtained are in disagreement with the view concerning frequent involvement of p53 antioncogene in chromosome 17p deletions.

Base Sequence↗