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)

Previous studies have implicated ADP-ribosylation in the mechanism of TNF cytotoxicity. In short-term 51Cr-release assays with several mouse and human tumor cell lines, the inhibitors aminobenzamide (ABA) and nicotinamide (NA) of ADP-ribosylation sensitized HER-2/neu-nonoverexpressing cells (CaOV-3 and MCF-7) but not HER-2/neu-overexpressing cells (SKOV-3 and SKBR-3) to TNF. However, both inhibitors alone or in combination with either TNF and/or actinomycin D (AD) caused similar effects on ADP-ribosylation rates of CaOV-3 and SKOV-3 cells after 4 h of treatment. This result suggests that ADP-ribosylation may not be involved in sensitizing these human tumor cells to TNF. Both ABA and NA decreased the TNF sensitivity of L929 cells and either increased or decreased TNF sensitivity of EMT-6 cells in the absence or presence of actinomycin D, respectively. Again, there was no correlation between ADP-ribosylation and TNF cytotoxicity in these mouse cell lines. Thus, modulation of TNF sensitivity by these inhibitors might be linked to a compromised repair mechanism distinct from the effects on ADP-ribosylation alone.
 ...
PMID:TNF cytotoxicity: effects of HER-2/neu expression and inhibitors of ADP-ribosylation. 791 50

It is not clear which growth factors are crucial for the survival, proliferation, and differentiation of pancreatic beta-cells. We used the relatively differentiated rat insulinoma cell line INS-1 to elucidate this issue. Responsiveness of the DNA synthesis of serum-starved cells was studied to a wide variety of growth factors. The most potent stimulators were PRL, GH, and betacellulin, a member of the epidermal growth factor (EGF) family that has not previously been shown to be mitogenic for beta-cells. In addition to these, only vascular endothelial growth factor, insulin-like growth factor-1 and -2, had significant mitogenic activity, whereas hepatocyte growth factor, nerve growth factor-beta, platelet-derived growth factors, basic fibroblast growth factor, EGF, transforming growth factor-alpha (TGF-alpha), neu differentiation factor, and TGF-beta were inactive. None of these factors affected the insulin content of INS-1 cells. In contrast, certain differentiation factors, including nicotinamide, sodium butyrate, activin A, and 1,25-dihydroxyvitamin D3 inhibited the DNA synthesis and increased the insulin content. Also all-trans-retinoic acid had an inhibitory effect on cell DNA synthesis but no effect on insulin content. From these findings betacellulin emerges as a novel growth factor for the beta-cell. Half-maximal stimulation of INS-1 DNA synthesis was obtained with 25 pM betacellulin. Interestingly, betacellulin had no effect on RINm5F cells, whereas both EGF and TGF-alpha were slightly mitogenic. These effects may possibly be explained by differential expression of the erbB receptor tyrosine kinases. In RINm5F cells a spectrum of erbB gene expression was detected (EGF receptor/erbB-1, erbB-2/neu, and erbB-3), whereas INS-1 cells showed only expression of EGF receptor. Expression of the erbB-4 gene was undetectable in these cell lines. In summary, our results suggest that the INS-1 cell line is a suitable model for the study of beta-cell growth and differentiation because the responses to previously identified beta-cell mitogens were essentially similar to those reported in primary cells. In addition, we have identified betacellulin as a possible modulator of beta-cell growth.
 ...
PMID:Growth factor-mediated proliferation and differentiation of insulin-producing INS-1 and RINm5F cells: identification of betacellulin as a novel beta-cell mitogen. 952 26

The erbB-2 gene encodes tyrosine kinase receptor p185(neu). Overexpression of erbB-2 plays a key role in tumorigenesis and the progression of tumors such as breast cancer and ovarian cancer. Our investigation suggests that the anti-inflammatory agent N-(4-ethoxyphenol)-2-hydroxy-acid amide (SUCI02) reversibly represses tyrosine phosphorylation of erbB-2 in a dose-dependent manner, with half maximal inhibition occurring at a concentration of 21.05 micromol/L without reduced erbB-2 receptor expression. Activation of mitogen-activated protein kinase and protein kinase B, downstream molecules of the erbB-2-mediated signal transduction pathway, was inhibited following exposure to SUCI02. In contrast, tyrosine phosphorylation of epidermal growth factor receptor (EGFR) was relatively unaffected by SUCI02. Proliferation of erbB-2-overexpressing BT474 cells was inhibited to a greater extent than proliferation of EGFR-overexpressing A431 cells following exposure to SUCI02. SUCI02 induced cell cycle arrest in G(1) phase with upregulation of p27 and downregulation of pRb phosphorylation. Systemic administration of SUCI02 in nude mice resulted in inhibition of erbB-2 tyrosine kinase phosphorylation of subcutaneous human breast cancer BT474 xenografts. We conclude that SUCI02 inhibits erbB-2 tyrosine kinase phosphorylation in vitro and in vivo, shuts down the erbB-2 downstream pathway and induces cell cycle arrest in G(1) phase. These results suggest that SUCI02 is a potential novel anticancer agent that deserves further investigation. (Cancer Sci 2006; 97: 84-89).
 ...
PMID:SUCI02 inhibits the erbB-2 tyrosine kinase receptor signaling pathway and arrests the cell cycle in G1 phase in breast cancer cells. 1636 26

The expression and activity of Fatty Acid Synthase (FASN; the sole enzyme capable of the reductive de novo synthesis of long-chain fatty acids from acetyl-CoA, malonyl-CoA, and nicotinamide adenine dinucleotide phosphate -NADPH-) is extremely low in nearly all nonmalignant adult tissues, whereas it is significantly up-regulated or activated in many cancer types, thus creating the potential for a large therapeutic index. Since the pioneering observation that inhibition of FASN activity by the mycotoxin cerulenin preferentially kills cancer cells and retards the growth of tumors in xenografts models, numerous in vitro and in vivo studies have confirmed the potential of FASN as a target for antineoplastic intervention. Other FASN inhibitors such as the cerulenin derivative C75, the beta-lactone orlistat, the green tea polyphenol epigallocatechin-3-gallate (EGCG) and other naturally occurring flavonoids (i.e., luteolin, quercetin, and kaempferol), as well as the antibiotic triclosan, have been identified and have been shown to limit cancer cell growth by inducing apoptotic cell death. Though the exact mode of action of these FASN inhibitors is under discussion, it has been revealed that depletion of end-product fatty acids, toxic intracellular accumulation of supra-physiological concentrations of the FASN substrate malonyl-CoA and/or limited membrane synthesis and/or functioning by altered production of phospholipids partitioning into detergent-resistant membrane microdomains (lipid raft-aggregates), can explain, at least in part, the cytostatic, cytotoxic as well as the apoptotic effects occurring upon pharmacological inhibition of FASN activity in cancer cells. Moreover, several cancer-associated molecular features including nonfunctioning p53, overexpression of the Her-2/neu (erbB-2) oncogene, and hyperactivation of the PI-3'K down-stream effector protein kinase B (AKT), appear to determine an exacerbated sensitivity to FASN inhibition-induced cancer cell death. Although few of these inhibitors are expected to be "exclusively" selective for FASN, the potential of FASN as a target for antineoplastic intervention has eventually been confirmed by RNA interference (RNAi)-knockdown of FASN. Certainly, future studies should definitely elucidate the ultimate biochemical link between FASN inhibition and cancer cell death. Although the combination of FASN structural complexity and until recently the lack of X-ray crystallography data of mammalian FASN created a significant challenge in the exploitation of FASN as a valuable target for drug development, it is hoped that the improvement in the selectivity and potency of forthcoming novel FASN-targeted small molecule inhibitors by taking advantage, for instance, of the recent 4.5 A resolution X-ray crystallographic map of mammalian FASN, will direct the foundation of a new family of chemotherapeutic agents in cancer history.
 ...
PMID:Pharmacological inhibitors of Fatty Acid Synthase (FASN)--catalyzed endogenous fatty acid biogenesis: a new family of anti-cancer agents? 1716 65

Reactive oxygen species (ROS) function as intracellular signaling molecules in a diverse range of biological processes. However, it is unclear how freely diffusible ROS dictate specific cellular responses. In this study, we demonstrate that nicotinamide adenine dinucleotide phosphate reduced oxidase 4 (Nox4), a major Nox isoform expressed in nonphagocytic cells, including vascular endothelium, is localized to the endoplasmic reticulum (ER). ER localization of Nox4 is critical for the regulation of protein tyrosine phosphatase (PTP) 1B, also an ER resident, through redox-mediated signaling. Nox4-mediated oxidation and inactivation of PTP1B in the ER serves as a regulatory switch for epidermal growth factor (EGF) receptor trafficking and specifically acts to terminate EGF signaling. Consistent with this notion, PTP1B oxidation could also be modulated by ER targeting of antioxidant enzymes but not their untargeted counterparts. These data indicate that the specificity of intracellular ROS-mediated signal transduction may be modulated by the localization of Nox isoforms within specific subcellular compartments.
 ...
PMID:Regulation of ROS signal transduction by NADPH oxidase 4 localization. 1857 11