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)

Expression of the RIalpha subunit of cAMP-dependent protein kinase type I is increased in human cancers in which an autocrine pathway for epidermal growth factor-related growth factors is activated. We have investigated the effect of sequence-specific inhibition of RIalpha gene expression on ovarian cancer cell growth. We report that RIalpha antisense treatment results in a reduction in RIalpha expression and protein kinase A type I, and inhibition of cell growth. The growth inhibition was accompanied by changes in cell morphology and appearance of apoptotic nuclei. In addition, EGF receptor, c-erbB-2 and c-erbB-3 levels were reduced, and the basal and EGF-stimulated mitogen-activated protein kinase activities were reduced. Protein kinase A type I and EGF receptor levels were also reduced in cells overexpressing EGF receptor antisense cDNA. These results suggest that the antisense depletion of RIalpha leads to blockade of both the serine-threonine kinase and the tyrosine kinase signaling pathways resulting in arrest of ovarian cancer cell growth.
 ...
PMID:Protein kinase A-Ialpha subunit-directed antisense inhibition of ovarian cancer cell growth: crosstalk with tyrosine kinase signaling pathway. 1049 Aug 35

We have tested the sensitivity of human MCF-10A mammary epithelial cells and of their transformed derivatives overexpressing an activated c-Ha-ras gene (MCF-10A Ha-ras cells), the c-erbB-2 gene (MCF-10A c-erbB-2 cells) or both genes (MCF-10A HE cells) to different cytotoxic drugs. As compared with parental MCF-10A cells, the transformed cells exhibited an increased sensitivity to topoisomerase I- and topoisomerase II-inhibitors, and to platinum-derivatives with a 2- to 10-fold reduction in IC(50) values. A remarkable difference in sensitivity was observed following treatment with taxanes. While MCF-10A Ha-ras cells showed an increased sensitivity, MCF-10A c-erbB-2 and MCF-10A HE cells exhibited a relative resistance to taxol and taxotere, with an approximately 3.5- to 6.5-fold higher IC(50) as compared with MCF-10A cells suggesting that c-erbB-2 overexpression has a dominant effect compared with an activated c-Ha-ras gene. The type I cAMP-dependent protein kinase (PKAI) is overexpressed in cancer cells. Inhibition of PKAI by antisense oligonucleotides targeting its RIalpha regulatory subunit results in cancer cell growth inhibition. To evaluate the effect of blocking PKAI on MCF-10A cell sensitivity to taxanes, we treated these cells with taxol or taxotere in combination with a PKAI antisense oligonucleotide. Treatment with this agent, but not with a control scramble sequence, was able to overcome the effect of c-erbB-2 overexpression on MCF-10A cell sensitivity to taxol and taxotere, with a 20- to 40-fold shift in the IC(50) values for the 2 drugs.
 ...
PMID:Resistance to taxanes is induced by c-erbB-2 overexpression in human MCF-10A mammary epithelial cells and is blocked by combined treatment with an antisense oligonucleotide targeting type I protein kinase A. 1069 53

Ansamycin antibiotics inhibit function of the heat shock protein (HSP) 90, causing selective degradation of several intracellular proteins regulating such processes as proliferation, cell cycle regulation, and prosurvival signaling cascades. HSP90 has been identified previously as a molecular target for anticancer agents, including ionizing radiation (IR). Therefore, we hypothesized that the ansamycin geldanamycin and its 17-allylamino-17-demethoxy analog (17-AAG), which inhibit HSP90, would enhance tumor cell susceptibility to the cytotoxicity of IR. Treatment of two human cervical carcinoma cell lines (HeLa and SiHa) with geldanamycin and 17-AAG resulted in cytotoxicity and, when combined with IR, enhanced the radiation response, each effect with a temporal range from 6 to 48 h after drug exposure. In addition, mouse in vivo models using 17-AAG at clinically achievable concentrations yielded results that paralleled the in vitro radiosensitization studies of both single and fractioned courses of irradiation. The increase in IR-induced cell death appears to be attributable to a combination of both programmed and nonprogrammed cell death. We also measured total levels of several prosurvival and apoptotic signaling proteins. Akt1, extracellular signal-regulated kinase-1, Glut-1, HER-2/neu, Lyn, cAMP-dependent protein kinase, Raf-1, and vascular endothelial growth factor expression were down-regulated in 17-AAG-treated cells, identifying these factors as molecular markers and potential therapeutic targets. Finally, a series of immortalized and human papillomavirus-transformed cell lines were used to demonstrate that the radiosensitizing effects of 17-AAG were limited to transformed cells, suggesting a possible differential cytotoxic effect. This work shows that altered HSP90 function induces significant tumor cytotoxicity and radiosensitization, suggesting a potential therapeutic utility.
 ...
PMID:Geldanamycin and 17-allylamino-17-demethoxygeldanamycin potentiate the in vitro and in vivo radiation response of cervical tumor cells via the heat shock protein 90-mediated intracellular signaling and cytotoxicity. 1469 17

In synthetic phenotype vascular smooth muscle cells (VSMC), activation of epidermal growth factor (EGF) receptor (EGFR) induces a sustained increase in intermediate conductance K(Ca) (int-K(Ca); K(Ca)3.1) channels that is essential for proliferation. However, a comparable mechanism has not been identified in native contractile phenotype VSMC, which express large conductance K(Ca) (maxi-K(Ca); K(Ca)1.1) channels, not int-K(Ca) channels. Using patch clamp of freshly isolated contractile VSMC from rat basilar artery, we found that EGF (100 ng ml(-1)) caused hyperpolarization (7.9 +/- 3.9 mV) due to activation of iberiotoxin-sensitive, maxi-K(Ca) channels. The EGFR ligands EGF (100 ng ml(-1)), transforming growth factor alpha (0.4 ng ml(-1)) and heparin-binding EGF (100 ng ml(-1)) all caused a 20% increase in maxi-K(Ca) channel current that was blocked by AG-1478 or by knock-down of EGFR expression using cisterna magna infusion of antisense oligodeoxynucleotide (AS-ODN). In controls, EGFR knock-down, and EGFR gain-of-expression (angiotensin II hypertension), the increase in maxi-K(Ca) current correlated with the abundance of EGFR protein expressed. The EGFR-mediated increase in maxi-K(Ca) channel activity was blocked by inhibiting cAMP-dependent protein kinase (cAK) using KT-5720 or Rp-cAMP, or by inhibiting adenylate cyclase type 5 (AC-5) using 2',5'-dideoxyadenosine or knock-down of AC-5 expression by intracisternal AS-ODN. Direct infusion of EGF into cisterna magna caused up-regulation of proliferating cell nuclear antigen (PCNA) in VSMC that was prevented by coinfusion of iberiotoxin or of AG-1478. Our data, which are consistent with the hypothesis that hyperpolarization is critical for a proliferative response, are the first to implicate AC-5 and maxi-K(Ca) channels in gene activation related to EGFR signalling in native contractile VSMC.
 ...
PMID:Adenylate cyclase 5 and KCa1.1 channel are required for EGFR up-regulation of PCNA in native contractile rat basilar artery smooth muscle. 1629 43


<< Previous 1 2