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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of fetal rat hepatocytes (FRH) with transforming growth factor beta 1 (TGF-beta 1) resulted in growth arrest and a biphasic effect on epidermal growth factor (EGF) receptor. After 2 h of exposure, EGF receptor (EGFR) was reduced by 43%. From 6 to 24 h, TGF-beta 1 exposure resulted in progressive increase in EGFR up to 74% over control. The increased binding was due to increase in high affinity EGF binding sites. FRH grown in medium containing EGF exhibited down-regulated EGFR with loss of high affinity EGF binding sites. With TGF-beta 1 exposure, high affinity EGFR was not down-regulated by EGF. Since down-regulation of EGFR involves internalization, the kinetics of EGF receptor-mediated endocytosis were examined. In TGF-beta 1-exposed FRH, EGF endocytosis was inhibited, with a reduction in the first order rate constant for the process from 0.078 to 0.043 min-1. Despite inhibition of growth, receptor down-regulation, and EGF endocytosis after TGF-beta 1 exposure, EGF-induced receptor autophosphorylation was preserved as demonstrated by [32P]phosphate-labeling of immunoprecipitated EGFR. These observations provide direct evidence that TGF-beta 1 regulates growth of fetal cells. Further, they suggest that TGF-beta 1 regulates endocytosis of EGF and possibly of other ligands.
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PMID:Transforming growth factor beta 1 inhibits epidermal growth factor receptor endocytosis and down-regulation in cultured fetal rat hepatocytes. 164 85

Transforming growth factor-alpha (TGF-alpha) is thought to be the major autocrine factor controlling growth in epidermal cells. To explore further the role of TGF-alpha in epidermal growth and differentiation, we used a human keratin K14 promoter to target expression of rat TGF-alpha cDNA to the stratified squamous epithelia of transgenic mice. Unexpectedly, the only regions of epidermis especially responsive to TGF-alpha overexpression were those that were normally thick and where hair follicle density was typically low. This included most, if not all, body skin from 2-day- to 2-week-old mice, and ear, footpad, tail, and scrotum skin in adult mice. In these regions, excess TGF-alpha resulted in thicker epidermis and more stunted hair growth. Epidermal thickening was attributed both to cell hypertrophy and to a proportional increase in the number of basal, spinous, granular, and stratum corneum cells. During both postnatal development and epidermal differentiation, responsiveness to elevated TGF-alpha seemed to correlate with existing epidermal growth factor (EGF) receptor levels, and we saw no evidence for TGF-alpha-mediated control of EGF receptor (EGFR) expression. In adults, no squamous cell carcinomas were detected, but benign papillomas were common, developing primarily in regions of mechanical irritation or wounding. In addition, adult transgenic skin that was still both sensitive to TGF-alpha and subject to mild irritation displayed localized regions of leukocytic infiltration and granular layer loss, characteristics frequently seen in psoriasis in humans. These unusual regional and developmental effects of TGF-alpha suggest a natural role for the growth factor in (1) controlling epidermal thickness during development and differentiation, (2) involvement in papilloma formation, presumably in conjunction with TGF-beta, and (3) involvement in psoriasis, in conjunction with some as yet unidentified secondary stimulus stemming from mild mechanical irritation/bacterial infection.
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PMID:Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation. 170 29

The hormone dependency of the MCF-7 breast cancer cell line, while extensively tested in liquid culture, has not been previously evaluated under conditions of anchorage-independent growth in serum-free media. Using the soft agar clonogenic assay, we demonstrate that physiologically relevant concentrations of estradiol (E2), progesterone (Pg), and prolactin (PRL) similarly stimulated MCF-7 cell colony formation in the absence of serum. Addition of an anti-insulin-like growth factor-I (IGF-I) antibody inhibited E2- and Pg-stimulated growth, while PRL action was not affected. Similar results were obtained with an anti-IGF-I receptor antibody, except that its inhibitory effect on Pg-induced colony formation was modest and not statistically significant. Administration of either an anti-transforming growth factor-alpha (TGF-alpha) antibody or an anti-epidermal growth factor (EGF) receptor antibody similarly inhibited E2-stimulated MCF-7 cell growth in soft agar, while neither antibody influenced Pg or PRL effects. Addition of TGF-beta 1, -beta 2, -beta 3 similarly suppressed MCF-7 cell colony formation in a dose dependent manner to a degree comparable to that observed with 4-OH-tamoxifen (4-OH-T). Furthermore, the growth inhibitory effect of 4-OH-T was completely reversed by an anti-TGF-beta antibody. We conclude that IGFs and TGF-alpha are important mediators of E2-stimulated MCF-7 cell growth in soft agar. IGFs may also be playing a role in Pg action, while neither growth factor is involved in PRL-stimulated colony formation. Finally, TGF-beta appears to be an important mediator of antiestrogen-induced inhibition of tumor growth.
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PMID:Growth factor involvement in the multihormonal regulation of MCF-7 breast cancer cell growth in soft agar. 181 68

In an attempt to understand the antiproliferative effects of progestins in endometrial cancer, we have examined the effects of the potent progestin, medroxyprogesterone acetate (MPA), on the cell proliferation and the expression of transforming growth factor (TGF) alpha and beta genes in human endometrial adenocarcinoma cell lines. The two cell lines used were Ishikawa, var 1, and HEC-50. In addition, the effects of exogenous TGF-alpha and anti-epidermal growth factor (EGF) receptor monoclonal antibody on cell proliferation were determined. Incubation of both cell lines with MPA resulted in a time- and dose-dependent inhibition of cell proliferation. Half-maximal growth inhibition was observed at 0.6 nM. In Ishikawa cells, the relative abundance of TGF-alpha was significantly reduced by MPA. A significant decrease in TGF-alpha mRNA was apparent 6 h after exposure to MPA and a further decrease was seen 12-24 h after addition of the progestin. The concentration of TGF-alpha immunoreactivity in conditioned medium of MPA-treated cells was also significantly reduced compared to control cultures. MPA had no effect on TGF-alpha expression by HEC-50 cells. EGF mRNA was not detected by Northern blot analysis in either cell type. MPA had no significant effect on EGF receptor mRNA abundance but resulted in a small increase in EGF receptor number in Ishikawa cells. Anti-EGF receptor monoclonal antibody (0.6-6 nM) inhibited Ishikawa cell growth but had no effect on HEC-50 cell proliferation. Exogenous TGF-alpha stimulated proliferation of both cell lines, but Ishikawa cells were significantly more sensitive to exogenous TGF-alpha than HEC-50 cells. Furthermore, TGF-alpha could reverse the growth inhibitory effects of MPA on Ishikawa cells. A decrease in TGF-beta mRNA abundance was also observed in MPA-treated Ishikawa and HEC-50 cells. This effect was of small magnitude, variable, and only observed after prolonged exposure to MPA. These observations are consistent with the hypothesis that the antiproliferative effects of progestins on Ishikawa cells are mediated by decreased expression and autocrine action of TGF-alpha. Since similar growth inhibition is also seen in the HEC-50 cells in which progestins have no effect on TGF-alpha expression, additional mechanisms are likely to be involved in the antiproliferative effects of progestins in human endometrial cancer.
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PMID:Transforming growth factor gene expression in human endometrial adenocarcinoma cells: regulation by progestins. 183 51

The polymerase chain reaction (PCR) was used to show that basic fibroblast growth factor (FGFb) and epidermal growth factor (EGF) receptor messenger ribonucleic acids (RNA) are produced in human lacrimal tissue. Transforming growth factor beta-1 (TGF beta-1) messenger RNA was not detected. These results and the previous identification of EGF in the lacrimal gland suggest that EGF could have autocrine or paracrine functions in lacrimal tissue. FGFb could also serve autocrine or paracrine functions in lacrimal gland physiology. It is also plausible that FGFb is released by the lacrimal gland into the tears and that the growth factor may have regulatory effects on the cells of the ocular surface.
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PMID:Basic fibroblast growth factor (FGFb) and epidermal growth factor (EGF) receptor messenger RNA production in human lacrimal gland. 189 78

We examined the effects of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) on EGF receptor (EGFR) phosphorylation and the expression of mRNAs for oncogenes, growth factors, their receptors and metalloproteinase genes by MKN-28 gastric carcinoma cells which express EGF, TGF-alpha and EGFR genes. Both EGF and TGF-alpha stimulated EGFR phosphorylation, EGF and TGF-alpha induced FOS, MYC and ERBB-2 oncogene expression. Interestingly, EGF increased the expression of mRNAs for TGF-alpha and EGFR. On the other hand, TGF-alpha increased TGF-alpha mRNA but decreased the expression of mRNAs for EGFR and TGF-beta. Furthermore, mRNAs for interstitial collagenase, stromelysin and procollagen type I genes were also enhanced after treatment with EGF and TGF-alpha. These results indicate that EGF and TGF-alpha successively evoke cascade phenomena which favor tumor progression, invasion and extracellular matrix formation, acting as autocrine growth regulators for gastric carcinomas.
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PMID:Induction of growth factor-receptor and metalloproteinase genes by epidermal growth factor and/or transforming growth factor-alpha in human gastric carcinoma cell line MKN-28. 216 68

We have examined the epidermal growth factor (EGF) dependence of the transcription of different proto-oncogenes, using cultured human mammary carcinoma MDA-468 cells and a nuclear run-on transcription assay. We found that the stimulation of MDA-468 cells with EGF regulates moderately and to different extents the transcription of the EGF-receptor(R) and c-erbB-2 proto-oncogenes. In contrast, the transcription of other proto-oncogenes, including c-myc, c-H-ras, and c-fps, was unchanged. Furthermore, we provide evidence that transforming growth factor beta 1 (TGF-beta 1) selectively and to different degrees modulates the EGF-dependent transcription of EGF-R and c-erbB-2 genes. In this study, we also discovered that T3 (triiodothyronine) exerts synergistic control on the action of EGF alone or in association with TGF-beta 1, on EGF-R and c-erbB-2 gene transcription. Moreover, we established that within 6 h after the addition of EGF, cytoplasmic EGF-R mRNA levels are increased several-fold and that this accumulation is enhanced by the presence of TGF-beta 1 and/or T3. The results described here are consistent with the hypothesis that a complex program of cooperative interactions among EGF-, TGF-beta 1-, and T3-generated signals at the transcriptional level may mediate, at least in part, the combined actions of EGF, TGF-beta 1, and T3 in target cells.
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PMID:Transcriptional regulation of proto-oncogene expression by epidermal growth factor, transforming growth factor beta 1, and triiodothyronine in MDA-468 cells. 256 27

The epidermal growth factor (EGF) receptor mediates the induction of a transformed phenotype in normal rat kidney (NRK) cells by transforming growth factors (TGFs). The ability of EGF and its analogue TGF-alpha to induce the transformed phenotype in NRK cells is greatly potentiated by TGF-beta, a polypeptide that does not interact directly with binding sites for EGF or TGF-alpha. Our evidence indicates that TGF-beta purified from retrovirally transformed rat embryo cells and human platelets induces a rapid (t 1/2 = 0.3 h) decrease in the binding of EGF and TGF-alpha to high-affinity cell surface receptors in NRK cells. No change due to TGF-beta was observed in the binding of EGF or TGF-alpha to lower affinity sites also present in NRK cells. The effect of TGF-beta on EGF/TGF-alpha receptors was observed at concentrations (0.5-20 pM) similar to those at which TGF-beta is active in promoting proliferation of NRK cells in monolayer culture and semisolid medium. Affinity labeling of NRK cells and membranes by cross-linking with receptor-bound 125I-TGF-alpha and 125I-EGF indicated that both factors interact with a common 170-kD receptor structure. Treatment of cells with TGF-beta decreased the intensity of affinity-labeling of this receptor structure. These data suggest that the 170 kD high-affinity receptors for EGF and TGF-alpha in NRK cells are a target for rapid modulation by TGF-beta.
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PMID:Transforming growth factor-beta modulates the high-affinity receptors for epidermal growth factor and transforming growth factor-alpha. 298 23

Various cytokines are involved in growth regulation of human melanoma cells. Malignant melanoma cells express multiple growth factors, including basic fibroblast growth factor (bFGF), transforming growth factor (TGF)-alpha, platelet-derived growth factor (PDGF)-alpha, and melanoma growth stimulatory activity (MGSA), substances which are not expressed in normal human melanocytes. The simultaneous synthesis of growth factors and expression of their receptors by melanoma cells, leading to permanent stimulation of cell proliferation, has been clearly shown for bFGF and MGSA. This phenomenon has been designated autocrine growth stimulation. Increased or altered expression of growth factor receptors has been described for nerve growth factor (NGF) receptor, for PDGF-beta receptor and for a truncated form of epidermal growth factor (EGF) receptor encoded by the c-erb-B2 oncogene. Lymphokines are mainly involved in growth control of melanoma cells. Interferons (IFN)-alpha, -beta and -gamma, Interleukins (IL)-1 and -6 as well as tumour necrosis factor (TNF)-alpha inhibited melanoma cell proliferation, with the strongest effects displayed by IFN. TGF-beta which was found to inhibit proliferation of normal human melanocytes exhibited marginal effects on melanoma cells, or even stimulated their growth. In conclusion, a complex network of cytokines is involved in the regulation of melanoma cell growth. Further insight into these mechanisms may contribute to the finding of new strategies in melanoma therapy.
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PMID:Cytokines in human melanoma cells: synthesis, autocrine stimulation and regulatory functions--an overview. 816 82

The regulation of cytokine production by thymic epithelial cells (TEC) in the thymus is under coordinated and temporal control and is important for the development of T cells. Human TEC express TGF-beta R and epidermal growth factor (EGF) receptor, and produce TGF-beta 3 in vitro and in vivo. Furthermore, EGF has been shown to increase IL-1 alpha, IL-1 beta, IL-6 mRNA and protein levels in human TEC. Since EGF has been shown to modulate TGF-beta effector functions, we determined whether TGF-beta can modulate EGF-mediated increases in cytokine gene expression in human TEC. We established that a single TEC expresses both EGF receptor and TGF-beta R. TGF-beta plus EGF synergistically increased leukemia-inhibitory factor (LIF), additively increased IL-6, but had little effect on IL-1 alpha and IL-1 beta mRNA levels. In contrast, TGF-beta alone increased LIF and IL-6, had little effect on IL-1 alpha, and slightly decreased IL-1 beta mRNA levels. The increases in LIF and IL-6 mRNA levels by TGF-beta plus EGF correlate with the increases in LIF and IL-6 concentrations in TEC culture supernatants as detected by ELISA. We also determined the mechanism responsible for the increases in cytokine mRNA levels. TGF-beta plus EGF did not affect transcription of LIF and IL-6 genes; this suggests that the increases in the steady state levels of cytokine mRNA were mediated post-transcriptionally, most likely at the level of mRNA stability. Our data demonstrate that TGF-beta modulates TEC cytokine production. We speculate that TGF-beta produced in situ plays a role in thymocyte development by directly affecting thymocyte differentiation and by indirectly modulating TEC cytokine production.
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PMID:TGF-beta differentially modulates epidermal growth factor-mediated increases in leukemia-inhibitory factor, IL-6, IL-1 alpha, and IL-1 beta in human thymic epithelial cells. 905 4


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