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)

All-trans retinoic acid (ATRA) has been previously shown to inhibit the proliferation of some human ovarian carcinoma cell lines, and this inhibition was accompanied by cellular changes that were indicative of differentiation (Caliaro et al, 1994). In this work, a pretreatment of these adenocarcinoma cells with ATRA, for their respective doubling time, enhanced cisplatin (CDDP) cytotoxicity in the cell ines that were sensitive to its antiproliferative effect, but not in the ATRA-resistant ones. Results were assessed using median effect analysis in two ATRA-sensitive cell lines (OVCCR1 and NIHOVCAR3 cells) and in one ATRA-insensitive cell line (IGROV1 cells). Synergy between these two agents was observed only in cells sensitive to ATRA, regardless of their relative sensitivity to CDDP. Potential mechanisms for this synergy were investigated. ATRA did not increase the cellular platinum content, did not decrease the cellular glutathione and had no influence on the metallothionein IIA mRNA levels in NIHOVCAR3 cells. Moreover, the protein kinase C (PKC) activity was modulated by this differentiating agent in all cell lines tested, indicating that this activity was not directly involved in this potentiation. However, an ATRA inhibition of glutathione-S-transferase activity associated with an increase in the total DNA adducts formation could explain the potentiation of the CDDP cytotoxicity observed in NIHOVCAR3 cells. Finally, the ATRA modulation of the epidermal growth factor (EGF) receptor mRNA level could also be implicated in this synergy.
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PMID:Multifactorial mechanism for the potentiation of cisplatin (CDDP) cytotoxicity by all-trans retinoic acid (ATRA) in human ovarian carcinoma cell lines. 902 Apr 76

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.
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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

We investigated the effects of all-trans retinoic acid (ATRA) and fenretinide (4-HPR) on c-erbB-2 expression in SK-BR-3, BT-474 and MCF-7 breast cancer cells and on the growth, differentiation, apoptosis and cisplatin (CDDP) sensitivity of SK-BR-3 cells. It has been reported that oestrogen inhibits c-erbB-2 in oestrogen receptor-positive breast cancer cells. Using ELISA, Western and Northern analysis we have demonstrated that ATRA and 4-HPR exert similar effects down-regulating c-erbB-2 protein and mRNA in c-erbB-2-overexpressing SK-BR-3 and BT-474 and in normally expressing MCF-7 cells. Both retinoids inhibit SK-BR-3 cell growth. ATRA induces cellular enlargement and flattening, suggesting epithelial differentiation. 4-HPR causes nuclear and cytoplasmic condensation, DNA fragmentation and externalization of phosphatidylserine, indicating apoptosis. c-erbB-2 expression/activity has been linked to sensitivity against CDDP. Therefore, combinations of ATRA or 4-HPR with CDDP were tested for their anti-proliferative activity. Retinoid-conditioned cells were either exposed to retinoid and CDDP (schedule I, 'continuous retinoid treatment') or to CDDP alone (schedule II, 'retinoid pretreatment'). This retinoid-conditioning followed by CDDP +/- retinoid yields stronger growth inhibition compared with unconditioned cells, which were exposed to CDDP +/- retinoid (schedule III, 'no retinoid pretreatment'). The inefficacy of schedule III indicates that retinoid-conditioning is essential for the improvement of the antiproliferative effect. The interactions in schedules I and II are synergistic for ATRA and CDDP, but slightly antagonistic for 4-HPR and CDDR However, 4-HPR + CDDP is more effective in growth inhibition than each drug alone.
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PMID:Effects of retinoic acid and fenretinide on the c-erbB-2 expression, growth and cisplatin sensitivity of breast cancer cells. 966 55

Nuclear retinoid and membrane c-erbB receptors participate in signal transduction systems that control mammary epithelial cell proliferation and differentiation. Recently, we demonstrated that c-erbB receptor activation stimulates retinoic acid receptor-alpha expression. We now report that retinoids reduce SK-BR-3 breast cancer cell growth by inhibiting the cell cycle and by inducing apoptosis. This is accompanied with reduced c-erbB expression as determined by FACS, Western, Northern, RT-PCR, and reporter assays. All-trans (ATRA) and 9-cis retinoic acid (9cRA) reduce c-erbB-1 protein to 50-100%, c-erbB-2 to 20-30%, and c-erbB-3 to 10-50% of control, depending on the concentration, respectively, without influencing the tyrosine phosphorylation status. Down-regulation of c-erbB-2 and -3 was seen at all levels analyzed, whereas c-erbB-1 mRNA remained unchanged. Retinoic acid-mediated down-regulation of growth and c-erbB-2 and -3 expression was also seen in MCF-7 cells. We conclude that retinoic acids are efficient repressors of c-erbB-2 and -3 gene expression, whereas c-erbB-1 is not markedly affected.
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PMID:Retinoids control the expression of c-erbB receptors in breast cancer cells. 979 Oct 9

The role of retinoic acid receptors (RARs) in intercellular regulation of cell growth was assessed by targeting a dominant-negative RARalpha mutant (dnRARalpha) to differentiated suprabasal cells of mouse epidermis. dnRARalpha lacks transcriptional activation but not DNA-binding and receptor dimerization functions. Analysis of transgenic mice revealed that dnRARalpha dose-dependently impaired induction of basal cell proliferation and epidermal hyperplasia by all-trans RA (tRA). dnRARalpha formed heterodimers with endogenous retinoid X receptor-alpha (RXRalpha) over RA response elements in competition with remaining endogenous RARgamma-RXRalpha heterodimers, and dose-dependently impaired retinoid-dependent gene transcription. To identify genes regulated by retinoid receptors and involved in cell growth control, we analyzed the retinoid effects on expression of the epidermal growth factor (EGF) receptor, EGF, transforming growth factor-alpha, heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin genes. In normal epidermis, tRA rapidly and selectively induced expression of HB-EGF but not the others. This induction occurred exclusively in suprabasal cells. In transgenic epidermis, dnRARalpha dose-dependently inhibited tRA induction of suprabasal HB-EGF and subsequent basal cell hyperproliferation. Together, our observations suggest that retinoid receptor heterodimers located in differentiated suprabasal cells mediate retinoid induction of HB-EGF, which in turn stimulates basal cell growth via intercellular signaling. These events may underlie retinoid action in epidermal regeneration during wound healing.
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PMID:Identification of heparin-binding EGF-like growth factor as a target in intercellular regulation of epidermal basal cell growth by suprabasal retinoic acid receptors. 1007 25

Nuclear steroid/retinoid and memgbrane c-erbB receptor tyrosine kinase signaling control proliferation and differentiation of mammary epithelial cells. Recently, we reported that retinoic acids are efficient repressors of c-erbB-2 and -3, but not of c-erbB-1 gene expresson. Here we demonstrate that retinoid acid- mediated growth inhibition is accompanied with reduced expression of c-erbB-4/HER4 in T47D breast cancer cells as determined by FACS, Western, and RT-PCR. All-trans and 9-cis retinoic acid reduce c-erbB-4 expression to 30%-60% of control, depending on the concentration. Dexamethasone (Dex) is inactive on D3 (D3), in contrast, acts as a strong inducer, elevation more that twofold at the mRNA, but does not significantly affect cell growth. We concolude that retinoic acids are efficient growth inhibitors and repressors of cell growth and c-erbB-4, whereas D3 represents a highly efficient inducer of c-erbB-4 expression with affecting cell proliferation.
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PMID:Expression of c-erbB-4/HER4 is regulated in T47D breast carcinoma cells by retinoids and vitamin D3. 1038 75

The effects of all-trans retinoic acid (ATRA) and epidermal growth factor (EGF) on the expression of nm23-H1, a metastasis suppressor gene, were studied in a human 7721 hepatocarcinoma cell line. It was discovered that the expression of nm23-H1 mRNA was up-regulated by ATRA. This was compatible with the observation that the metastasis-associated phenotypes, such as chemotaxic cell migration and invasion, were both reduced in the ATRA-treated and nm23-H1-cDNA-transferred 7721 cells. However, ability of cells to adhere to fibronectin and laminin was not altered identically in the ATRA-treated and nm23-H1-cDNA-transfected 7721 cells. In contrast, the expression of nm23-H1 mRNA in 7721 cells was down-regulated both by the treatment with EGF and by the transfection of c-erbB-2/neu cDNA, which codes a protein homologous to the EGF receptor. EGF is a compound with biological effects opposite to those of ATRA, and c-erbB-2/neu is known to be a metastasis-promoting gene. These results reveal that the metastasis-preventing effect of ATRA may partly result from the up-regulation of nm23-H1, and the metastasis-promoting effects of EGF and c-erbB-2/neu were probably mediated in part by the down-regulation of nm23-H1.
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PMID:Effects of all-trans retinoic acid and epidermal growth factor on the expression of nm23-H1 in human hepatocarcinoma cells. 1066 47

Nuclear steroid/thyroid/retinoid receptors and c-erbB membrane receptor tyrosine kinases control epithelial growth and differentiation. Retinoid receptors can dimerize with the vitamin D receptor, the glucocorticoid receptor or the thyroid receptor. Furthermore, multiple c-erbB receptor dimers have been identified. It has been shown that some of these receptor pathways communicate with each other via cross-connected regulatory networks. Molecular interactions between retinoid receptors or estrogen receptors (ER) and c-erbB-2, and between ER and retinoic acid receptor(RAR)-alpha have been reported. Here, we demonstrate the effects of steroids/thyroids/retinoids and of activators of protein kinase A (forskolin, Forsk) and C (12-O-tetradecanoylphorbol-13-acetate, TPA), on growth and expression of c-erbB and RARs in MCF-7 breast cancer cells, which contain high levels of RAR-alpha and -gamma, and which express significant amounts of c-erbB-2 and -3. All trans-retinoic acid (tRA), the anti-estrogen ICI 182 780 (ICI), Forsk and TPA reduced, whereas triiodothyronine and 17beta-estradiol (E2) stimulated cell growth. Flow cytometry revealed that tRA and E2 reduced c-erbB-2 and -3, whereas tamoxifen, Forsk and TPA up-regulated c-erbB-2. c-erbB-3 was co-regulated with c-erbB-2. Northern analysis demonstrated that RAR-alpha was down-regulated by dexamethasone, ICI, and TPA, whereas vitamin D3 and E2 up-regulated RAR-alpha. RAR-gamma expression was less responsive to such treatment, being reduced only by ICI and Forsk. These data indicate that nuclear receptor and protein kinase signaling communicate with each other and control the expression of RARs and c-erbB receptors. Efficient growth control requires the coordinated interplay of both receptor systems.
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PMID:Involvement of nuclear steroid/thyroid/retinoid receptors and of protein kinases in the regulation of growth and of c-erbB and retinoic acid receptor expression in MCF-7 breast cancer cells. 1067 83

An important role for beta-catenin pathways in colorectal carcinogenesis was first suggested by the protein's association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of beta-catenin protein expression at all stages of the adenoma-carcinoma sequence. Recent studies have, however, shown that yet more components of colorectal carcinogenesis are linked to beta-catenin pathways. Pro-oncogenic factors that also release beta-catenin from the adherens complex and/or encourage translocation to the nucleus include ras, epidermal growth factor (EGF), c-erbB-2, PKC-betaII, MUC1, and PPAR-gamma, whereas anti-oncogenic factors that also inhibit nuclear beta-catenin signaling include transforming growth factor (TGF)-beta, retinoic acid, and vitamin D. Association of nuclear beta-catenin with the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors promotes the expression of several compounds that have important roles in the development and progression of colorectal carcinoma, namely: c-myc, cyclin D1, gastrin, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-7, urokinase-type plasminogen activator receptor (aPAR), CD44 proteins, and P-glycoprotein. Finally, genetic aberrations of several components of the beta-catenin pathways, eg, Frizzled (Frz), AXIN, and TCF-4, may potentially contribute to colorectal carcinogenesis. In discussing the above interactions, this review demonstrates that beta-catenin represents a key molecule in the development of colorectal carcinoma.
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PMID:Beta-catenin--a linchpin in colorectal carcinogenesis? 1183 57

Aberrant proliferation is an early-occurring event in vitro prior to tumorigenesis in vivo in the multistep process of carcinogenesis. Inhibition of aberrant proliferation therefore may represent a useful biomarker to evaluate the efficacy of chemopreventive agents. Retinoids have exhibited preventive efficacy in vitro and in vivo predominantly through the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Clinically relevant biochemical and cellular mechanistic endpoints for chemopreventive effects of retinoids should provide novel biomarkers. The present study was designed to examine the preventive efficacy of natural retinoids, all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9cisRA), and to identify the possible mechanisms for their effects using the HER-2/neu oncogene expressing preneoplastic human mammary epithelial 184-B5/HER cells. Seven-day treatment with ATRA and 9cisRA exhibited a dose-dependent growth inhibition. Long-term (21 days) treatment with IC20 doses of 50 nM ATRA and 100 nM 9cisRA inhibited anchorage-dependent colony forming efficiency by about 75.4% (p<0.01) and 84.9% (p<0.01), respectively. Cell cycle analysis revealed that a 24-h treatment with IC90 doses of 2 microM ATRA and 3 microM 9cisRA accumulates cells in the G0/G1 phase and inhibit S and/or G2/M phase of the cell cycle. ATRA and 9cisRA induced an 11-fold (p=0.03) and a 9-fold (p=0.04) increase in subG0/G1 (apoptotic) population relative to the solvent control, respectively. ATRA and 9cisRA induced 77% (p=0.01) and 51% (p=0.02) decrease in tyrosine kinase immunoreactivity, respectively. Similarly, the two retinoids caused almost a 50% (p=0.01) down-regulation of Bcl-2 immunoreactivity. Western blot analysis revealed that ATRA induced an increase in RARbeta expression and a decrease in RARgamma expression, while 9cisRA down-regulated RXRalpha expression. These data demonstrate that ATRA and 9cisRA may inhibit HER-2/neu induced aberrant proliferation in part by retarding cell cycle progression, down-regulating HER-2/neu-mediated signal transduction and inducing Bcl-2-dependent apoptosis through a retinoid receptor-mediated mechanism.
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PMID:Preventive efficacy of receptor class selective retinoids on HER-2/neu oncogene expressing preneoplastic human mammary epithelial cells. 1206 59


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