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)

Retinoic acid and dexamethasone have antagonistic effects on epidermal growth factor (EGF) receptor expression in fetal rat lung (FRL) cells: Receptor synthesis is enhanced by retinoic acid and reduced by dexamethasone. In the presence of actinomycin D, neither agent has the capacity to modify receptor synthesis or 125I-EGF binding capacity. Northern blot analysis demonstrates a tenfold increase in EGF mRNA following retinoic acid treatment and a 60% decrease in receptor message levels after dexamethasone treatment. To dissect the mechanisms of these effects, the expression of mRNA was separated from effects requiring protein synthesis by the use of cycloheximide and actinomycin D. Ligand binding, EGF receptor protein synthesis, and mRNA levels were measured in cultures of FRL cells that were incubated with retinoic acid or dexamethasone in the presence of cycloheximide, then washed and reincubated with fresh media containing actinomycin D, but not retinoic acid, dexamethasone, or cycloheximide. The results demonstrate that dexamethasone reduces the expression of EGF receptor mRNA in the absence of protein synthesis. In contrast, the mechanism by which retinoic acid increases the expression of EGF receptor mRNA requires protein synthesis. These data indicate that, in FRL cells, dexamethasone negatively regulates EGF receptor mRNA in a direct manner, while retinoic acid controls transcription of an intermediate protein, possibly a transcription factor, that subsequently increases transcription of receptor message.
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PMID:Dexamethasone and retinoic acid regulate the expression of epidermal growth factor receptor mRNA by distinct mechanisms. 174 17

Levels of epidermal growth factor (EGF) receptor expression vary widely among cell lines derived clonally from a chemically transformed population of rat liver epithelial cells. Retinoic acid (RA), a derivative of vitamin A that stimulates differentiation in a number of embryonal cell lines, increases the level of 125I-EGF binding in several clones of the transformed cell lines. One such cell line, GP6ac, which reverts to a less transformed phenotype when treated with RA, exhibited a 3-4-fold increase in surface EGF receptors with prolonged (2-5-day) RA exposure. The increase persisted as long as the cells were treated with RA. The increase in surface EGF receptors was due to induction of receptor biosynthesis, which occurred within 4 h at both the mRNA and protein levels and persisted until the RA was withdrawn. Paradoxically, the RA response was accompanied by an initial 40-50% decrease in 125I-EGF binding during the first 12 h of RA treatment. The decrease was due primarily to a reduction of receptor affinity. Since the phorbol ester 12-O-tetradecanoylphorbol-13-acetate also decreases 125I-EGF binding and increases EGF receptor biosynthesis in GP6ac cells, we tested the effect of RA in cells depleted of protein kinase C by prolonged treatment (18 h) with 10 microM 12-O-tetradecanoylphorbol-13-acetate. The absence of protein kinase C did not affect the induction of receptor mRNA and protein or the decrease in binding during the early period of RA exposure. This indicates that RA induction of EGF receptor synthesis in GP6ac cells involves signaling pathways distinct from those utilized by phorbol esters.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of epidermal growth factor receptor induction by retinoic acid in a chemically transformed rat liver cell line. 228 80

The effects of retinoic acid on the epidermal growth factor (EGF) receptor binding and cell growth of normal and simian virus 40 (SV40)-transformed BALB/c 3T3 cells were compared under identical culture conditions. Retinoic acid induced a rapid enhancement of EGF binding to SV40-transformed cells. Half-maximal enhancement occurred at about 7 h after the cells were exposed to 20 ng/ml of retinoic acid, and maximal stimulation (from 2.5- to 3.5-fold over the control) was obtained after 12 h of exposure. The kd of the control and retinoic acid-treated cells was calculated to be 8.0 X 10(-10) M and 8.2 X -10 M, respectively. However, the number of unoccupied EGF binding sites increased from 0.98 X 10(4) to 2.28 X 10(4) per cell. Normal 3T3 cells would not respond to retinoic acid unless they were cultured in serum-containing medium. After 96 h of exposure, only a 50% enhancement of EGF binding was observed. The EGF receptor number of the untreated normal cells was calculated to be 1.82 X 10(4) per cell, twice the number expressed by untreated SV40-transformed cells. The increase of EGF receptor number caused by retinoic acid in SV40-transformed cells was blocked by either actinomycin D or cycloheximide treatment. These results indicated that SV40 transformation of BALB/c 3T3 cells altered the regulatory mechanism governing the complement of cell surface EGF receptors.
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PMID:Differential responsiveness of normal and simian virus 40-transformed BALB/c 3T3 cells to retinoic acid: rapid enhancement of epidermal growth factor receptor binding in a simian virus 40-3T3 variant. 304 Feb 36

Retinoids are potent regulators of epithelial cell growth and differentiation. Recently, they have been demonstrated to be effective in the treatment of preneoplastic cervical lesions in which human papillomavirus (HPV) is expressed. To better understand the mechanism of the antineoplastic effect of retinoic acid on HPV-positive cells, the effects of retinoic acid on both normal and HPV-immortalized human ectocervical epithelial cell growth, epidermal growth factor (EGF) receptor level, and EGF receptor function were investigated. Both HPV-immortalized cells (ECE16-1) and normal ectocervical cells (ECE cells) are growth stimulated by EGF. ECE16-1 but not normal ectocervical epithelial cells are growth inhibited by trans-retinoic acid which attenuates the stimulatory effect of EGF on ECE16-1 cell growth. Retinoic acid reduces both EGF binding and EGF receptor protein levels in ECE16-1 cells but not in normal ectocervical cells. The reduction in EGF receptor binding and receptor protein levels in ECE16-1 cells is not associated with the induced secretion of a soluble EGF receptor ligand, altered EGF receptor affinity, receptor internalization, or decreased receptor stability. Interestingly, the level of EGF receptors is consistently elevated in the ECE16-1 cell line as compared to normal ectocervical epithelial cells. Investigation of a second HPV-immortalized cell line (ECE16-D1) and two other HPV-positive cervical carcinoma cell lines revealed similar elevated EGF-binding capacity and regulation by retinoic acid. In contrast, two HPV-negative cervical carcinoma cell lines demonstrated various EGF-binding levels but demonstrated no significant loss of EGF binding following retinoic acid treatment. Other normal cells and an SV40 large T-antigen-immortalized foreskin keratinocyte cell line, KER-1, had EGF receptor levels similar to the normal ectocervical epithelial cells, and no regulation by retinoic acid was observed. These data indicate that HPV immortalization may increase EGF receptor levels in ectocervical cells, elevating their sensitivity to growth stimulation by EGF, and that retinoic acid can possibly attenuate this increased responsiveness to EGF.
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PMID:Human papillomavirus 16 immortalization of normal human ectocervical epithelial cells alters retinoic acid regulation of cell growth and epidermal growth factor receptor expression. 840 22

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 growth of human breast tumor cells is regulated through signaling involving cell surface growth factor receptors and nuclear receptors of the steroid/thyroid/retinoid receptor gene family. Retinoic acid receptors (RARs), members of the steroid/thyroid hormone receptor gene family, are ligand-dependent transcription factors, which have in vitro and in vivo growth inhibitory activity against breast cancer cells. RAR-agonists inhibit the proliferation of many human breast cancer cell lines, particularly those whose growth is stimulated by estradiol (E2) or growth factors. Additionally, RAR-agonists and synthetic retinoids such as Ferentinide have been shown to induce apoptosis in malignant breast cells but not normal breast cells. To better define the genes involved in RAR-mediated growth inhibition of breast cancer cells, we used oligonucleotide microarray analysis to create a database of genes that are potentially regulated by RAR-agonists in breast cancer cells. We found that PDCD4 (programmed cell death 4), a tumor suppressor gene presently being evaluated as a target for chemoprevention, was induced about three-fold by the RARalpha-selective agonist Am580, in T-47D breast cancer cells. RAR pan-agonists and Am580, but not retinoid X receptors (RXR)-agonists, stimulate the expression of PDCD4 in a wide variety of retinoid-inhibited breast cancer cell lines. RAR-agonists did not induce PDCD4 expression in breast cancer cell lines, which were not growth inhibited by retinoids. We also observed that antiestrogen and the HER-2/neu antagonist, Herceptin (Trastuzumab), also induced PDCD4 expression in T-47D cells, suggesting that PDCD4 may play a central role in growth inhibition in breast cancer cells. Transient overexpression of PDCD4 in T-47D (ER+, RAR+) and MDA-MB-231 (ER-, RAR-) cells resulted in apoptotic death, suggesting a role for PDCD4 in mediating apoptosis in breast cancer cells. PDCD4 protein expression has previously been reported in small ductal epithelium of normal breast. To date, there has been no report of induction of PDCD4 expression by RAR-agonists, antiestrogen or HER2/neu antagonist in breast cancer cells and its potential role in apoptosis in these cells.
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PMID:Induction of PDCD4 tumor suppressor gene expression by RAR agonists, antiestrogen and HER-2/neu antagonist in breast cancer cells. Evidence for a role in apoptosis. 1536 28

Retinoic acid (RA) induces cell cycle arrest of hormone-dependent human breast cancer (HBC) cells. Previously, we demonstrated that RA-induced growth arrest of T-47D HBC cells required the activity of the RA-induced protein kinase, protein kinase Calpha (PKCalpha) [J. Cell Physiol. 172 (1997) 306]. Here, we demonstrate that RA treatment of T-47D cells interfered with growth factor signaling to downstream, cytoplasmic and nuclear targets. RA treatment did not inhibit epidermal growth factor (EGF) receptor activation but resulted in rapid inactivation. The lack of sustained EGFR activation was associated with transient rather than sustained association of the EGFR with the Shc adaptor proteins and activation of Erk 1/2 and with compromised induction of expression of immediate early response genes. Inhibiting the activity of PKCalpha, a retinoic acid-induced target gene, prevented the effects of RA on cell proliferation and EGF signaling. Constitutive expression of PKCalpha, in the absence of RA, decreased cell proliferation and decreased EGF signaling. RA treatment increased steady-state levels of the protein tyrosine phosphatase PTP-1C and all measured effects of RA on EGF receptor function were reversed by the tyrosine phosphate inhibitor orthovanadate. These results indicate that RA-induced target genes, particularly PKCalpha, prevent sustained growth factor signaling, uncoupling activated receptor tyrosine kinases and nuclear targets that are required for cell cycle progression.
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PMID:Retinoids arrest breast cancer cell proliferation: retinoic acid selectively reduces the duration of receptor tyrosine kinase signaling. 1553 Aug 51