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)

Activator Protein (AP)-2 is a transcription factor that is required for mouse development. AP-2 activates expression of positive and negative growth regulators including erbB-2 and p21 WAF1/CIP1. Induction of p21 has been correlated with cell cycle and growth inhibition of human cancer cells. Because several endogenous AP-2 binding sites do not fit the known consensus sequences well, we sought to define AP-2's interaction with DNA more precisely. Using Cyclic Amplification and Selection of Targets (CAST'ing) of random oligonucleotide sequences and recombinant human AP-2 protein, we identified 17 novel AP-2 binding sites. Mobility shift assays showed significant AP-2 binding of the novel sites as compared to p21, erbB-2 and hMtIIa sites. Several sites that bound with high specificity and affinity did not fit known AP-2 consensus sequences. A sequence comparison based on several of the novel sequences yielded a putative consensus binding sequence of 5'-TAGAAAGNYCYNG-3'. These DNA binding sites may help identify novel targets of AP-2 and aid in further understanding AP-2 function.
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PMID:Identification of a novel AP-2 consensus DNA binding site. 947 23

Differences in therapeutic outcomes after regional chemotherapy or chemo-immunotherapy in liver metastases from colorectal carcinoma cannot be explained only by variations in the regimens of treatment. This study was undertaken to assess the potential of several tumor-associated markers of biological behavior (biomarkers) to predict therapeutic response in order to pre-select the best candidates for this demanding treatment. In a group of 21 patients, flow cytometric DNA ploidy provided the most accurate prediction, with a response rate of 88% in 8 DNA diploid tumors compared to 31% in 13 DNA aneuploid cases (P = 0.017) and a difference in overall survival of nine months (20.4 vs 11.3, P = 0.041). Only a slight trend towards improved response rate was observed when we immunohistochemically detected p53 anti-oncoprotein expression in 11 (52%) p53-positive tumors (P = 0.063). Other immunohistochemical biomarkers as P-glycoprotein (p170), p21/WAF, mdm2, c-erbB-2, and proliferative activity of tumor (detected either by anti-PCNA and anti-Ki67 monoclonal antibodies or as a flow cytometric proliferation index) were unrelated to the outcome of treatment. DNA ploidy and expression of p53 protein are potential biomarkers for predicting the response to regional chemotherapy of liver metastases from colorectal carcinoma.
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PMID:Biomarkers for predicting response to regional chemo-immunotherapy in liver metastases from colorectal carcinoma. 963 42

This recent symposium featured speakers from several clinical and research disciplines. Among the findings: peptic ulcer disease is a significant predisposing risk factor (odds ratio = 3.9) for pancreatic cancer; as many as 50% of all intraductal papillary mucinous neoplasms are associated with invasive adenocarcinomas; alteration of gene expression via methylation of a gene promotor region constitutes a potentially reversible method of tumor suppressor gene inactivation; > 400 transcriptional alterations of gene expression have been identified for pancreatic cancer; some common molecular markers such as p53 and HER-2/neu may be related to morphologic alterations of in situ neoplasia and to transcriptional alterations of gene expression rather than mutational events; epidermal growth factor (EGF), transforming growth factor beta (TGF-beta), and related molecules may modulate gene transcription via "autocrine" or "paracrine" mechanisms; several cytokines, amylin (islet amyloid polypeptide), and other cachexia factors are responsible for paraneoplastic peripheral insulin resistance, ineffective utilization of glucose, and profound cachexia. In the clinical diagnostic arena: the World Health Organization established a standard nomenclature for intraductal papillary mucinous neoplasms, mucinous cystic tumors, intraductal mucinous hyperplasias, and solid pseudopapillary tumors; focal glandular differentiation may be commonly identified within pancreatic endocrine neoplasms (islet cell tumors) while not necessarily implying an unfavorable prognosis typical of ductal adenocarcinomas; positron emission tomography scanning may be used for evaluation of early tumor response to novel chemotherapeutic regimens; helical computed tomography (CT) is the state of the art in preoperative imaging for pancreatic cancer; neoadjuvant 5-fluorouracil (5-FU)-based chemoradiation in 39 "resectable" patients provided a median survival of 19 months, actuarial 4-year survival of 19%, and improved local tumor control; gemcitabine has shown promise in alleviating tumor-related symptoms with a significantly better "clinical benefit response" than single agent 5-FU (23.8 vs. 4.8%, p = 0.0022) based on change in pain intensity, daily analgesic consumption, performance status, and weight; a significant survival advantage was demonstrated in patients treated with conventional therapies whose tumors expressed p21WAF-1, an important inhibitor of cell cycle progression and downstream molecule of p53 and TGF-beta; a p21-adenovirus (rAD-p21) gene therapy resulted in significant growth inhibition of pancreatic cancer cell lines in tissue culture, and development of a successful SCID mouse-human pancreatic adenocarcinoma xenograft model provided an animal model for preclinical trials of rAD-p21.
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PMID:Current concepts in pancreatic cancer: symposium summary. 982 Nov 73

Ectopic expression of decorin induces profound cytostatic effects in transformed cells with diverse histogenetic backgrounds. The mechanism of action has only recently begun to be elucidated. Exogenous decorin activates the epidermal growth factor (EGF) receptor, thereby triggering a signaling cascade that leads to phosphorylation of mitogen-activated protein (MAP) kinase, induction of p21, and growth suppression. In this study we demonstrate a direct interaction of decorin with the EGF receptor. Binding of decorin induces dimerization of the EGF receptor and rapid and sustained phosphorylation of MAP kinase in squamous carcinoma cells. In a cell-free system, decorin induces autophosphorylation of purified EGF receptor by activating the receptor tyrosine kinase and can also act as a substrate for the EGF receptor kinase itself. Using radioligand binding assays we show that both immobilized and soluble decorin bind to the EGF receptor ectodomain or to purified EGF receptor. The binding is mediated by the protein core and has relatively low affinity (Kd approximately 87 nM). Thus, decorin should be considered as a novel biological ligand for the EGF receptor, an interaction that could regulate cell growth during remodeling and cancer growth.
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PMID:Decorin is a biological ligand for the epidermal growth factor receptor. 998 78

Epidemiology suggests a possible relationship between exposure to power frequency magnetic fields (EMF) and breast cancer. One mechanism through which EMF could stimulate breast cancer induction is via altered expression of oncogenes and/or tumor suppressor genes that regulate normal and neoplastic growth. To evaluate the hypothesis that EMF action in the breast is mediated by alterations in gene expression, transcript levels of c-myc and a battery of other cancer-associated genes were quantitated in human breast epithelial cells exposed to pure, linearly polarized 60 Hz EMF with low harmonic distortion. HBL-100 cells and normal (non-transformed) human mammary epithelial cells were exposed to EMF flux densities of 0.1, 1.0 and 10.0 Gauss (G) for periods ranging from 20 min to 24 h; concurrent sham controls were exposed to ambient fields (<0.001 G) only. Gene expression was quantitated using ribonuclease protection assays. EMF exposure had no statistically significant effect on basal levels of c-myc transcripts in either human breast cell model, and had no effect on alterations in c-myc expression induced by 12-O-tetradecanoylphorbol-13-acetate. Transcript levels of c-erbB-2, p53, p21, GADD45, bax, bcl-x, mcl-1, and c-fos were also unaffected by EMF exposure. These results suggest that EMF is unlikely to influence breast cancer induction through a mechanism involving altered expression of these genes.
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PMID:Gene expression in human breast epithelial cells exposed to 60 Hz magnetic fields. 1042 19

Dok (for downstream of tyrosine kinases) proteins are a newly identified family of docking molecules that are characterized by the presence of an amino-terminal pleckstrin homology (PH) domain, a central putative phosphotyrosine-binding (PTB) domain and numerous potential sites of tyrosine phosphorylation [1] [2] [3] [4] [5] [6]. Here, we explore the potential role of the Dok family member Dok-R (also known as p56(Dok2) or FRIP) in signaling pathways mediated by the epidermal growth factor (EGF) receptor. An intact PTB domain in Dok-R was critical for its association with two PTB-binding consensus sites on the EGF receptor and the PH domain further contributed to stable in vivo binding and tyrosine phosphorylation of Dok-R. Multiple sites on Dok-R were tyrosine-phosphorylated following EGF stimulation; phosphorylated Tyr276 and Tyr304 are proposed to dock the tandem Src homology 2 (SH2) domains of the p21(Ras) GTPase-activating protein rasGAP and Tyr351 mediates an association with the SH2 domain of the adapter protein Nck. Interestingly, we have found that Dok-R could attenuate EGF-stimulated mitogen-activated protein (MAP) kinase activation independently of its association with rasGAP. Together, these results suggest that Dok-R has an important role downstream of growth factor receptors as a potential negative regulator of signal transduction.
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PMID:Recruitment of Dok-R to the EGF receptor through its PTB domain is required for attenuation of Erk MAP kinase activation. 1050 18

The study was carried out on 53 patients who had thyroid cancer with various degree of differentiation. We studied the expression of bcl-2, a-erbB-2, p53, and p21 ras protein. The protein encoded by bCL-2 proto-oncogene is implicated in the prolongation of cell survival by blocking programmed cell death, i.e. apoptosis. The role of p53 and bcl-2 genes in the regulation of apoptosis has important implications in oncogenesis. Wild-type p53 is thought to promote apoptosis, whilst mutant p53 has a similar effect on apoptosis as bcl-2 that is inhibition of programmed cell kinase activity. C-erb-2 protein overexpression is currently being evaluated as a potential risk factor in breast cancer patients? The ras gene family codes for a 21 kD protein (p21), which binds guanine nucleotides and possesses GTPase activity. Through this mechanism, the ras p21 protein participates in the control of cell proliferation, possibly as a signal transducer from cell surface receptors to the nucleus. Activation of ras genes has been implicated in neoplastic transformation of cells. The aim of our study is to evaluate the expression of these markers in thyroid carcinomas. All immunohistochemical study was performed in paraffin-embedded tissues pathology specimen. Any well differentiated tumor in our study was positive for bcl-2 protein. C-erb-2 immunostaining was present in tumor samples in 60% of cases. In most cases, specific membrane staining as well as a weak cytoplasmic positivity of tumor cells were seen. Immunoreactivity for p53 was positive only in 10% of cases. By immunostaining, p21 protein was expressed in 55% of the 53 tumors tested, with different degree of expression. Only some poorly differentiated tumours were positive for bcl-2, furthermore all markers tested were strongly positive in these tumours. In conclusion, our results indicate that bcl-2, c-erbB-2, p53, and p21 ras protein are differently expressed in thyroid carcinomas in relation to the degree of aggressiveness and differentiation.
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PMID:Expression of bcl-2, c-erbB-2, p53, and p21 (waf1-cip1) protein in thyroid carcinomas. 1060 83

Human papillomavirus (HPV) 16 has previously been found in 19/41 breast carcinomas (46%) in women with a history of HPV 16 positive CIN III lesions. There was no significant difference in distribution of histological subtypes, mean or median tumour diameter or number of regional lymph node metastases in the HPV positive and HPV negative breast carcinoma groups. P53, p21 and c-erbB-2 proteins were analysed by immunohistochemistry in the HPV 16 positive and HPV negative breast carcinomas. There was a significant difference in p53 and p21 protein immunoreactivity between HPV 16 positive and HPV negative breast carcinomas (p = 0.0091 and p = 0.0040), with a significant less detectable p53 and p21 protein immunoreactivity in the HPV 16 positive cases. There was also a significant difference in the coexpression of p53/p21 between the HPV 16 positive and HPV 16 negative breast carcinomas (p = 0.002). No significant difference in immunostaining for c-erbB-2 protein in the two groups was found (p = 0.15), or for the coexpression of p53/c-erbB-2 (p = 0.19). The significantly lower expression of p53 and p21 proteins in HPV 16 positive than in HPV 16 negative breast carcinomas supports the hypothesis of inactivation and degradation of wild-type p53 proteins by HPV 16 E6 and that p53 mutation is not necessary for transformation in the HPV 16 positive cases.
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PMID:Significant difference in p53 and p21 protein immunoreactivity in HPV 16 positive and HPV negative breast carcinomas. 1060 22

p21(WAF1/CIP1) is transcriptionally activated by wt p53 and inhibits G1 associated cyclins, a major mechanism by which p53 inhibits cellular proliferation. Archival breast cancers (798) with a median follow-up of 16.3 years were used to explore the prognostic value of p21 immunohistochemical analyses. p21 immunostaining was detected in the majority (726/798: 91%) of breast cancers as well as adjacent in situ carcinomas (125/170: 74%), hyperplastic lesions (140/349: 40%) and normal breast epithelium adjacent to carcinoma (3/89: 3%). Complete immunonegativity was observed in only 9% of invasive cancers and was associated with p53 immunopositivity (p < 0.05). Univariate analysis of all patients showed that p21 negativity was associated with a longer disease specific survival (relative risk (RR) 1.5). Node positive p21- patients also showed a longer disease free and disease specific survival as compared to tumor p21+ patients. In node negative patients, p53 positivity but not p21 alone, was significantly associated with a shortened disease free survival (RR = 1.6). Node negative patients who were p53+ p21-, in particular had the shortest disease free survival compared to other p53, p21 subgroups (i.e., p21 negativity was associated with a worse outcome). Multivariate analysis of lymph node negative patients (n > 300) demonstrated that tumor size and tumor grade were independently predictive of outcome, whereas neither p53 nor p21 were significant. For node positive patients, p21 positivity (p = 0.05), p53 positivity (p = 0.03), a higher number of positive nodes, larger tumor size, steroid receptor negativity, high proliferation rate, and erbB-2 expression were each independently associated with poor outcome. In summary, p21 negativity was inversely correlated with p53 immunopositivity in the majority of cases. p21 negative tumor patients had an improved outcome if they were node positive, whereas p21 status was not significantly associated with survival in node negative patients. This observation may be due to the reported 'uncoupling of S phase and mitosis' associated with a loss of p21 expression which may result in enhanced sensitivity to chemotherapy.
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PMID:p(21WAF1/CIP1) expression in breast cancers: associations with p53 and outcome. 1093 88

Azoxymethane (AOM)-induced colonic carcinogenesis involves a number of mutations, including those in the K-ras gene and CTNNB1, that codes for beta-catenin. Prior in vitro studies have also demonstrated that wild type p21(K-ras) can be activated by epigenetic events. We identified 15 K-ras mutations in 14 of 84 AOM-induced colonic tumors by three independent methods. By single strand conformational polymorphism, we also observed mutations in 22 of 68 tumors in exon 3 of CTNNB1. A highly sensitive method was then used to measure p21ras activation levels. All tumors assayed possessing K-ras mutations had significantly higher p21ras activation levels (8.8 +/- 1.5%; n = 13) compared with that of control colon (3.7 +/- 0.4; n = 6; P < 0.05) or tumors without such mutations (4.2 +/- 0.4%; n = 70; P < 0.05). Among tumors with wild-type K-ras, there was a subset of tumors (18 of 70) that had significantly higher p21ras activation levels (8.0 +/- 0.9%; n = 18) compared with control colons. In three of four tumors examined with activated wild-type p21ras, we observed increased c-erbB-2 receptor expression and decreased Ras-GAP expression. In contrast, only one of eight tumors examined with wild-type ras and nonactivated p21ras demonstrated these alterations. Mitogen-activated protein kinase (MAPK) activation and cyclooxygenase-2 (COX-2) expression were increased in tumors with mutated or activated wild-type p21ras, compared with their nonactivated counterparts. Although beta-catenin mutations did not alter COX-2 expression or MAPK activity, mutations in either K-ras or beta-catenin significantly increased cyclin D1 expression. In contrast, in tumors with wild-type but activated p21-ras, cyclin D1 expression was not enhanced. Thus, the spectrum of changes in MAPK, COX-2, and cyclin D1 is distinct among tumors with ras or beta-catenin mutations or nonmutational activation of p21ras.
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PMID:Mutational and nonmutational activation of p21ras in rat colonic azoxymethane-induced tumors: effects on mitogen-activated protein kinase, cyclooxygenase-2, and cyclin D1. 1096 13


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