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

Epithelial cells from non-cancerous mammary tissue in response to exposure to chemical carcinogens or transfection with oncogenes exhibit hyperproliferation and hyperplasia prior to the development of cancer. Aberrant proliferation may, therefore, represent a modifiable early occurring preneoplastic event that is susceptible to chemoprevention of carcinogenesis. The synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR), has exhibited preventive efficacy in several in vitro and in vivo breast cancer models, and represents a promising chemopreventive compound for clinical trials. Clinically relevant biochemical and cellular mechanisms responsible for the chemopreventive effects of HPR, however, are not fully understood. Experiments were performed on preneoplastic human mammary epithelial 184-B5/HER cells derived from reduction mammoplasty and initiated for tumorigenic transformation by overexpression of HER-2/neu oncogene, to examine whether HPR inhibits aberrant proliferation of these cells and to identify the possible mechanism(s) responsible for the inhibitory effects of HPR. Continuous 7-day treatment with HPR produced a dose-dependent, reversible growth inhibition. Long-term (21 day) treatment of 184-B5/HER cells with HPR inhibited anchorage-dependent colony formation by approximately 80% (P < 0.01) relative to that observed in the solvent control. A 24 h treatment with cytostatic 400 nM HPR produced a 25% increase (P = 0.01) in G0/G1 phase, and a 36% decrease (P = 0.01) in S phase of the cell cycle. HPR treatment also induced a 10-fold increase (P = 0.02) in the sub-G0 (apoptotic) peak that was down-regulated in the presence of the antioxidant N-acetyl-L-cysteine. Treatment with HPR resulted in a 30% reduction of cellular immunoreactivity to tyrosine kinase, whereas immunoreactivity to p185HER remained essentially unaltered. HPR exposure resulted in time-dependent increase in cellular metabolism of the retinoid as evidenced by increased formation of the inert metabolite N-(4-methoxyphenyl)-retinamide (MPR) and progressive increase in apoptosis. Thus, HPR-induced inhibition of aberrant proliferation may be caused, in part, by its ability to inhibit HER-2/neu-mediated proliferative signal transduction, retard cell cycle progression and upregulate cellular apoptosis.
 ...
PMID:Inhibition of aberrant proliferation and induction of apoptosis in HER-2/neu oncogene transformed human mammary epithelial cells by N-(4-hydroxyphenyl)retinamide. 1006 58

Epithelial mucins are large, secreted and cell surface glycoproteins involved in epithelial cell protection, adhesion modulation, and signaling. Using differential display, we have identified two novel mucin cDNAs (dd34 and dd29), hereafter designated MUC11 and MUC12, respectively, that are down-regulated in colorectal cancers. Northern blots demonstrated polydisperse signals characteristic of mucin transcripts in RNA from normal colon that were absent in colorectal cancer. Both cDNAs were mapped by fluorescence in situ hybridization to chromosome band 7q22, the location of the MUC3 mucin gene, thus suggesting that there may be a cluster of mucin genes at this locus. The sequences of both differential display clones were extended by a combination of screening libraries and PCR. The 2.8-kb MUC11 cDNA composite encoded 35 serine/threonine-rich, mucin-like degenerate 28 amino acid tandem repeats. The MUC12 cDNA composite encoded a putative transmembrane mucin containing two extracellular cysteine-rich, EGF-like domains, a coiled-coil region, and a mucin-like domain consisting of 28 amino acid degenerate tandem repeats. Distinct patterns of expression of MUC11, MUC12, and MUC3 mRNAs were observed in a range of normal human tissues. MUC12 mRNA was not expressed in any of six colorectal cancer cell lines examined and was down-regulated or absent in 6 of 15 (40%) tumors compared with matched normal colonic tissue. In contrast, MUC11 showed a different pattern of mRNA expression, with four of these lines showing low levels and the other two lines showing relatively high levels of MUC11 transcripts. Expression of MUC11 was down-regulated in the tumors of 12 of 15 (80%) paired samples. Structural homology of MUC12 with rat, mouse, and human MUC3 and human and rat MUC4/ASGP2 indicate that there is a distinct subfamily of transmembrane mucins with conserved epidermal growth factor domains. The homology of MUC12 with epidermal growth factor-like growth factors and its down-regulation in colorectal cancers, together with known interactions between rat MUC4 and c-erbB-2 growth factor receptors, suggests that MUC12 may be involved in epithelial cell growth regulation.
 ...
PMID:Two novel mucin genes down-regulated in colorectal cancer identified by differential display. 1046 11

Metallothionein (MT) is a low molecular weight, cysteine-rich, zinc-binding protein that may have a function in cellular repair processes, growth and differentiation. Using a monoclonal antibody (E9) to metallothionein, we investigated the immunohistochemical expression of MT in routinely fixed and paraffin-embedded tissue from 98 cases of female breast carcinomas. The MT expression was studied in comparison with the expression of the basement membrane (BM) antigens (type IV collagen, laminin), fibronectin, cathepsin D, adhesion molecule CD44, p53 protein, the pRb, c-erbB-2 oncoprotein, EGFR, stromelysin-1, proliferation indices (Ki-67, PCNA), steroid receptor content as well as with other conventional clinicopathological parameters of breast cancer. Strong MT expression was observed in the majority of tumour cells in 18.4% of tumours, focal MT positivity in 13.3% and almost complete lack of MT expression in 68.4% of cases (mean value 33.36 +/- 26.36). The MT expression in carcinoma cells was strongly associated with the DCIS component of the tumour (p < 0.0001). High values of MT were correlated with low steroid receptor status (p = 0.08 for ER receptor and p = 0.019 for PgR receptor content). MT positive cases were correlated with stromelysin-1 expression (p = 0.059) and cathepsin D (p = 0.058). These findings suggest that MT expression is characteristic of the early phase of breast carcinogenesis, possibly regulated by hormones, and could be a new potential prognostic marker in breast cancer.
 ...
PMID:Immunohistochemical localization of metallothionein in human breast cancer in comparison with cathepsin D, stromelysin-1, CD44, extracellular matrix components, P53, Rb, C-erbB-2, EGFR, steroid receptor content and proliferation. 1047 Jan 61

Amplification and overexpression of erbB-2/neu is an important determinant in the initiation and progression of human breast cancer. Indeed, transgenic mice that over-express the neu proto-oncogene heritably develop mammary adenocarcinomas. Tumorigenesis in these transgenic strains is associated with activation of the intrinsic catalytic activity of Neu. In many of these tumors, activation of Neu occurs as a result of somatic mutations located within the transgene itself. Examination of the altered neu transcripts revealed the presence of in-frame deletions that encode aberrant Neu receptors lacking 5 to 12 amino acids within the extracellular domain proximal to the transmembrane region of Neu. In addition to these deletion mutants we have also detected single point mutations within this juxta-transmembrane region. The majority of the mutations analyzed affect the one of several conserved cysteine residues present within this region. Introduction of these activating mutations into the wild-type neu cDNA results in its oncogenic conversion. Taken together, these observations suggest that this cysteine-rich region plays an important role in regulating the catalytic activity of Neu.
 ...
PMID:Oncogenic activating mutations in the neu/erbB-2 oncogene are involved in the induction of mammary tumors. 1066 81

The trefoil peptide intestinal trefoil factor (ITF) plays a critical role in the protection of colonic mucosa and is essential to restitution after epithelial damage. These functional properties are accomplished through coordinated promotion of cell migration and inhibition of apoptosis. ITF contains a unique three-looped trefoil motif formed by intrachain disulfide bonds among six conserved cysteine residues, which is thought to contribute to its marked protease resistance. ITF also has a seventh cysteine residue, which permits homodimer formation. A series of cysteine-to-serine substitutions and a C-terminally truncated ITF were made by PCR site-directed mutagenesis. Any alteration of the trefoil motif or truncation resulted in loss of protease resistance. However, neither an intact trefoil domain nor dimerization was required to promote cell migration. This pro-restitution activity correlated with the ability of the ITF mutants to activate mitogen-activated protein (MAP) kinase independent of phosphorylation of the epidermal growth factor (EGF) receptor. In contrast, only intact ITF retained both phosphatidylinositol 3-kinase and the EGF receptor-dependent antiapoptotic effect in HCT116 and IEC-6 cells. The inability to block apoptosis correlated with a loss of trefoil peptide-induced transactivation of the EGF receptor or Akt kinase in HT-29 cells. In addition to defining structural requirements for the functional properties of ITF, these findings demonstrate that distinct intracellular signaling pathways mediate the effects of ITF on cell migration and apoptosis.
 ...
PMID:Distinct pathways of cell migration and antiapoptotic response to epithelial injury: structure-function analysis of human intestinal trefoil factor. 1084 94

We investigated the ubiquitination and degradation of a tumor antigen, the HER-2/neu (HER-2) protooncogene product which is overexpressed in epithelial cancers. HER-2 degradation was investigated in the ovarian tumor line, SKOV3.A2, that constitutively overexpressed long-life HER-2. We used as agonist geldanamycin (GA), which initiated downmodulation of HER-2 from the cell surface. HER-2 was polyubiquitinated and degraded faster in the presence than in the absence of GA. GA did not decrease HLA-A2 expression. Presentation of the immunodominant cytotoxic T lymphocyte (CTL) epitope, E75 (369-377) from SKOV.A2 was inhibited by proteasome inhibitors, such as LLnL but was enhanced by cysteine protease inhibitors such as E64, indicating that both the proteasome and cysteine proteases are involved in epitope formation but have different effects. Enhanced tumor recognition was not an immediate or early effect of GA treatment, but was evident after 20 h of GA treatment. In contrast, 20 h GA treatment did not increase tumor sensitivity to LAK cell lysis. Twenty hour GA-treated SKOV3.A2 cells expressed an unstable HER-2 protein synthesized in the presence of GA, of faster electrophoretic mobility than control HER-2. This suggested that the newly synthesized HER-2 in the presence of GA was the main source of epitopes recognized by CTL. Twenty hour GA-treated SKOV3.A2 cells were better inducers of CTL activity directed to a number of HER-2 CTL epitopes, in peripheral blood mononuclear cells compared with control untreated SKOV3.A2 cells. Thus, induction of HER-2 protein instability enhanced the sensitivity of tumor for CTL lysis. Increased HER-2 CTL epitopes presentation may have implications for overcoming the poor immuno-genicity of human tumors, and design of epitope precursors for cancer vaccination.
 ...
PMID:Accelerated HER-2 degradation enhances ovarian tumor recognition by CTL. Implications for tumor immunogenicity. 1126 62

Cross-communication between different signaling systems allows the integration of the great diversity of stimuli that a cell receives under varying physiological situations. In this paper we have explored the possibility that tumor necrosis factor (TNF) receptor signal cross-talks with epidermal growth factor (EGF) receptor signal on the nuclear factor-kappa B (NF-kappa B) activation pathway. We have demonstrated that overexpression of the EGF receptor (EGFR) in NIH3T3 cells significantly enhances TNF-induced NF-kappa B-dependent luciferase activity even without EGF, that EGF treatment has a synergistic effect on the induction of the reporter activity, and that this enhancement is suppressed by AG1478, EGFR-specific tyrosine kinase inhibitor. We also have shown that TNF induces tyrosine phosphorylation and internalization of the overexpressed EGFR in NIH3T3 cells and the endogenously expressed EGFR in A431 cells and that the transactivation by TNF is suppressed by N-acetyl-l-cysteine or overexpression of an endogenous reducing molecule, thioredoxin, but not by phosphatidylinositol 3-kinase inhibitors and protein kinase C inhibitor. Taken together, this evidence strongly suggests that EGFR transactivation by TNF, which is regulated in a redox-dependent manner, is playing a pivotal role in TNF-induced NF-kappa B activation.
 ...
PMID:Redox-sensitive transactivation of epidermal growth factor receptor by tumor necrosis factor confers the NF-kappa B activation. 1133 89

HER3 (also known as c-Erb-b3) is a type I receptor tyrosine kinase similar in sequence to the epidermal growth factor (EGF) receptor. The extracellular segment of this transmembrane receptor contains four domains. Domains I and II are similar in sequence to domains III and IV, respectively, and domains II and IV are cysteine-rich. We show that the EGF-like domain of heregulin (hrg) binds to domains I and II of HER3, in contrast to the EGF receptor, for which prior studies have shown that a construct consisting of domains III and portions of domain IV binds EGF. Next, we identified a putative hrg binding site by limited proteolysis of the recombinant extracellular domains of HER3 (HER3-ECD(I-IV)) in both the presence and absence of hrg. In the absence of hrg, HER3-ECD(I-IV) is cleaved after position Tyr(50), near the beginning of domain I. Binding of hrg to HER3-ECD(I-IV) fully protects position Tyr(50) from proteolysis. To confirm that domain I contains a hrg binding site, we expressed domains I and II (HER3-ECD(I-II)) and find that it binds hrg with 68 nm affinity. These data suggest that domains I and II of HER3-ECD(I-IV) act as a functional unit in folding and binding of hrg. Thus, our biochemical findings reinforce the structural hypothesis of others that HER3-ECD(I-IV) is similar to the insulin-like growth factor-1 receptor (IGF-1R), as follows: 1) The protected cleavage site in HER3-ECD(I-IV) corresponds to a binding footprint in domain I of IGF-1R; 2) HER3-ECD(I-II) binds hrg with a 68 nm dissociation constant, supporting the hypothesis that domain I is involved in ligand binding; and 3) the large accessible surface area (1749 A) of domain L1 of IGF-1R that is buried by domain S1, as well as the presence of conserved contacts in this interface of type 1 RTKs, suggests that domains L1 and S1 of IGF-1R function as a unit as observed for HER3-ECD(I-II). Our results are consistent with the proposal that HER3 has a structure similar to IGF-1R and binds ligand at a site in corresponding domains.
 ...
PMID:Identification of a heregulin binding site in HER3 extracellular domain. 1155 49

Chemokines are a family of proteins that have pleiotropic biological effects. They are well known to regulate the recruitment and trafficking of leukocytes to sites of inflammation. Chemokines are grouped into four classes based on the positions of key cysteine residues: C, CC, CXC, and CX3C. Stromal cell-derived factor-1 (SDF-1), the ligand of the CXCR4 receptor, is a CXC chemokine and is a highly conserved gene. Ovarian cancer typically disseminates widely in the abdomen, a characteristic that limits curative therapy. The mechanisms that promote ovarian cancer proliferation are incompletely understood. We studied a human ovarian adenocarcinoma cell line (OC 314) and investigated the role of CXCR4 activation by SDF-1 in human ovarian cancer. We demonstrate that CXCR4 and SDF-1 mRNA are expressed in OC 314. We show that SDF-1alpha induces proliferation in ovarian cancer cells in a dose-dependent manner. Moreover, we demonstrate that the SDF-1-dependent proliferation correlates to the phosphorylation and activation of extracellular signal-regulated kinases (ERK)1/2, which in turn are correlated to epidermal growth factor (EGF) receptor transactivation. In fact, AG1478, a specific inhibitor of the EGF receptor kinase, blocked both SDF-1alpha-dependent proliferation and ERK1/2 activation.
 ...
PMID:CXCR4 activation induces epidermal growth factor receptor transactivation in an ovarian cancer cell line. 1565 94

Connective tissue growth factor (CTGF/CCN2) is a cysteine-rich matricellular protein that belongs to the CCN (CYR61, CTGF, NOV) protein family. It is highly expressed by human rhabdomyosarcoma cells and sustains their survival. In this study we investigated CCN2 expression in a mouse model of spontaneous rhabdomyosarcomagenesis that combines HER-2/neu oncogene activation and p53 oncosuppressor gene inactivation (BALB-p53neu mice). Murine rhabdomyosarcoma cells showed a 4-26 fold increase in CCN2 mRNA expression regarding to normal thigh muscle. Moreover, they expressed CCN2 protein at levels comparable to human rhabdomyosarcoma cells. Therefore BALBp53neu mice might be useful for the evaluation of the role played by CCN2 in rhabdomyosarcoma in vivo.
 ...
PMID:Expression of connective tissue growth factor (CTGF/CCN2) in a mouse model of rhabdomyosarcomagenesis. 1815 69


<< Previous 1 2