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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A synchrony between the activated state of the blastocyst and differentiation of the uterus to the receptive state is essential to the process of implantation. This process is directed by progesterone (P4) and estrogen. The mechanism by which P4 differentiates the uterus, enabling estrogen to initiate implantation, is unknown but likely to involve localized induction of growth and differentiation factors. We have cloned the murine amphiregulin (AR) gene, a newly discovered member of the epidermal growth factor family, and demonstrate that its expression is implantation-specific and P4-regulated in the mouse uterus. A transient surge in AR mRNA levels occurred throughout the uterine epithelium on day 4 of pregnancy. With the onset of blastocyst attachment late on day 4, AR mRNA accumulated in the luminal epithelium exclusively at the sites of blastocysts. Thus, AR expression correlated first with rising P4 levels and then with the attachment reaction. The rapid induction of AR mRNA in the ovariectomized uterus only by P4 and abrogation of this induction by RU-486 (a P4 receptor antagonist) suggest that this uterine gene is regulated by P4. AR appeared to exhibit preferential phosphorylation of epidermal growth factor receptor in the uterus over that in the blastocyst. This is a first report of a P4-regulated uterine epithelial cell growth factor that is associated with epithelial cell differentiation during implantation. The association of AR in implantation is further documented by its down-regulation in the day 4 pregnant uterus in which uterine receptivity and implantation were disrupted by estrogen or RU-486 treatment on day 3. These results further indicate that the expression of the AR gene could serve as a molecular marker for the receptive state of the uterus for implantation.
Mol Endocrinol 1995 Jun
PMID:Amphiregulin is an implantation-specific and progesterone-regulated gene in the mouse uterus. 859 15

Transforming growth factor-alpha (TGF alpha), a member of the epidermal growth factor receptor ligand family, has been implicated in the regeneration and transformation of liver. Our recent development of mice that are homozygous for a disrupted TGF alpha gene allowed us to assess the requirement for this growth factor in these complex processes. We report here that although a 70% hepatectomy produced a significant increase in hepatic TGF alpha protein levels in wild-type mice, liver regeneration nevertheless proceeded normally in the absence of the growth factor. The hepatocyte labeling indices determined for homozygous targeted and wild-type mice at 36 and 48 h after hepatectomy were comparable, and the total liver DNA to body weight ratios 8 d after hepatectomy were essentially identical for the two genotypes. These results indicate that TGF alpha, is not necessary for liver regeneration. To test its requirement in liver carcinogenesis, young mice were administered single doses of diethylnitrosamine (DEN) with or without subsequent chronic treatment with the promoting agent phenobarbital (PB). Both wild-type and homozygous mutant male mice treated with DEN or DEN plus PB developed multiple preneoplastic foci or tumors by 9 mo of age with relatively high incidence. However, while five of 88 tumors in wild-type mice attained a diameter greater than 5 mm and were classified as hepatocellular carcinomas, none of 132 tumors in livers of targeted mice reached this size. Furthermore, three of these large wild-type tumors expressed significantly elevated levels of TGF alpha protein compared with normal liver. These results indicate that TGF alpha is not required for early events in chemically induced hepatocarcinogenesis but suggest that it could be important in the progression from small preneoplastic foci to large tumors.
Mol Carcinog 1996 Mar
PMID:Liver regeneration and hepatocarcinogenesis in transforming growth factor-alpha-targeted mice. 859 31

Transforming growth factor-alpha (TGF-alpha) stimulates cell proliferation through interaction with its receptor, the epidermal growth factor receptor (EGFR), by activating its tyrosine kinase activities. The simultaneous overexpression of TGF-alpha and EGFR by tumor cells is thought to trigger the autocrine growth pathway, leading to uncontrolled proliferation. To examine their roles in rat esophageal tumorigenesis induced by the chemical carcinogen N-nitrosomethylbenzylamine (NMBA), TGF-alpha, and EGFR expression was evaluated in normal rat esophageal epithelium, in NMBA-induced preneoplastic lesions, and in papillomas by quantitative reverse transcription-polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemical analyses. Compared with the levels in normal epithelium, the TGF-alpha and EGFR mRNA levels in esophageal papillomas were 3.6 and 1.9 times higher, respectively. In the preneoplastic epithelium, although a trend of increased TGF-alpha and EGFR mRNA levels was observed, collectively there were no significant differences between preneoplastic and normal samples by RT-PCR analysis. In situ hybridization and immunohistochemical staining showed increased levels of TGF-alpha and EGFR mRNA and protein products in papillomas and in pronounced hyperplastic and dysplastic lesions. TGF-alpha and EGFR expression correlated with each other and with the expression of proliferating cell nuclear antigen, a marker for cell proliferation. These results suggest that disregulation of TGF-alpha and EGFR expression may contribute to autonomous cell growth and may play an important role in rat esophageal tumorigenesis induced by NMBA.
Mol Carcinog 1996 Feb
PMID:Alterations in transforming growth factor-alpha and epidermal growth factor receptor expression during rat esophageal tumorigenesis. 859 81

The intracellular localization of Shc proteins was analyzed by immunofluorescence and immunoelectron microscopy in normal cells and cells expressing the epidermal growth factor receptor or the EGFR/erbB2 chimera. In unstimulated cells, the immunolabeling was localized in the central perinuclear area of the cell and mostly associated with the cytosolic side of rough endoplasmic reticulum membranes. Upon epidermal growth factor treatment and receptor tyrosine kinase activation, the immunolabeling became peripheral and was found to be associated with the cytosolic surface of the plasma membrane and endocytic structures, such as coated pits and endosomes, and with the peripheral cytosol. Receptor activation in cells expressing phosphorylation-defective mutants of Shc and erbB-2 kinase showed that receptor autophosphorylation, but not Shc phosphorylation, is required for redistribution of Shc proteins. The rough endoplasmic reticulum localization of Shc proteins in unstimulated cells and their massive recruitment to the plasma membrane, endocytic structures, and peripheral cytosol following receptor tyrosine kinase activation could account for multiple putative functions of the adaptor protein.
Mol Cell Biol 1996 May
PMID:Sch proteins are localized on endoplasmic reticulum membranes and are redistributed after tyrosine kinase receptor activation. 862 61

Two chimeric receptors, ER1 and ER2, were constructed. ER1 contains the extracellular and transmembrane (TM) domains derived from epidermal growth factor receptor and the cytoplasmic domain from c-Ros; ER2 is identical to ER1 except that its TM domain is derived from c-Ros. Both chimeras can be activated by epidermal growth factor and are capable of activating or phosphorylating an array of cellular signaling proteins. Both chimeras promote colony formation in soft agar with about equal efficiency. Surprisingly, ER1 inhibits while ER2 stimulates cell growth on monolayer culture. Cell cycle analysis revealed that all phases, in particular the S and G2/M phases, of the cell cycle in ER1 cells were elongated whereas G1 phase of ER2 cells was shortened threefold. Comparison of signaling pathways mediated by the two chimeras revealed several differences. Several early signaling proteins are activated or phosphorylated to a higher extent in ER1 than in ER2 cells in response to epidermal growth factor. ER1 is less efficiently internalized and remains tyrosine phosphorylated for a longer time than ER2. However, phosphorylation of the 66-kDa She protein, activation of mitogen activated protein kinase, and induction of c-fos and c-jun occur either to a lesser extent or for a shorter time in ER1 cells. Cellular protein phosphorylation patterns are also different in ER1 and ER2 cells. In particular, a 190-kDa Shc-associated protein is tyrosine phosphorylated in ER2 but not in ER1 cells. Our results indicate that the TM domains have a profound effect on the signal transduction and biological activity of those chimeric receptors. The results also imply that sustained stimulation of ER1 due to its retarded internalization apparently triggers an inhibitory response that dominantly counteracts the receptor-mediated mitogenic signals. These two chimeras, expressed at similar levels in the same cell type but having opposite effects on cell growth, provide an ideal system to study the mechanism by which a protein tyrosine kinase inhibits cell growth.
Mol Cell Biol 1996 Apr
PMID:Two chimeric receptors of epidermal growth factor receptor and c-Ros that differ in their transmembrane domains have opposite effects on cell growth. 865 24

The present study was undertaken to determine the expression of the genes for epidermal growth factor receptor (EGF-R), and two of its ligands, epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) in isolated large (LLC) and small (SLC) porcine luteal cells by reverse transcription-polymerase chain reaction (RT-PCR), and to localize their peptides in whole corpora lutea (CL) as well in isolated LLC and SLC by immunocytochemistry. RT-PCR revealed strong cDNA signals for EGF-R and EGF in both LLC and SLC, and for TGF-alpha in LLC. The signal for TGF-alpha message in SLC was relatively weaker but detectable. Immunocytochemistry revealed intense EGF-R staining in LLC and SLC in both isolated and intact CL preparations. On the other hand, immunoreactive EGF and TGF-alpha appeared to be present only in LLC in intact CL sections, and isolated luteal cell preparations confirmed their presence in LLC and absence in SLC. These results suggest an autocrine/paracrine role for EGF and TGF-alpha in luteal functions.
Mol Cell Endocrinol 1995 Sep 22
PMID:Gene expression and peptide localization for epidermal growth factor receptor and its ligands in porcine luteal cells. 867 21

During the shift from a proliferative to a secretory endometrium in the rhesus menstrual cycle, progesterone action causes massive metabolic and structural remodelling. In order to identify genes whose expression is potentially important for the change from estrogen (E) to progesterone (P) dominance we have initiated a study of specific gene regulation using semiquantitative, reverse transcription polymerase chain reaction (RT-PCR). PolyA+ RNA was isolated from both E-dominant (days 9-13 of artificial menstrual cycles [AMCs]) and P-dominant (days 21-23) rhesus monkey endometria. The two pools of mRNA were converted to cDNA, end-ligated to double-stranded oligonucleotide adaptors and amplified by PCR using an adaptor-complementary primer. This procedure resulted in the production of E- and PcDNA template populations for cDNA-specific screening and comparative quantitation by PCR. Initial analysis showed that placental protein 14 (PP14) was P-dependent and human complement 3 (HC3) was up-regulated in E-dominant tissue, whereas the housekeeping genes B-actin and glyceraldehyde-3-phosphate dehydrogenase (G-3-PDH) were expressed at equivalent levels under E and P dominance. Expression of the E receptor (ER), P receptor (PR), epidermal growth factor receptor (EGFR) and insulin-like growth factor (IGF-I) was equivalent under E or P dominance. Expression of epidermal growth factor (EGF) and retinoblastoma (RB) was down-regulated in P-dominant tissue. Conversely IGF-1 receptor (IGF-1-R), transforming growth factor-beta 2 (TGFB-2), TGFB-2 receptor (TGFB-2-R), 17 beta-hydroxysteroid dehydrogenase (17-B-HSD) and leukemia inhibitory factor (LIF) levels were up-regulated in PcDNA. Among these factors, PP14, LIF, IGF-1-R TGFB-2 and 17-B-HSD were also detectable in PCR in a P-dependent cDNA library isolated by subtractive hybridization. These data provide evidence for hormonal regulation of specific gene products that may play important roles in the normal maturation of the primate endometrium in preparation for implantation.
Mol Cell Endocrinol 1995 Nov 30
PMID:Differential gene regulation by estrogen and progesterone in the primate endometrium. 867 69

The overexpression of epidermal growth factor receptor (EGFr) has been implicated as a causative factor and a poor prognostic marker in a number of carcinomas. Therefore, strategies that down-regulate EGFr expression may be therapeutically useful. We designed antisense ODNs complementary to the initiation codon region of the EGFr mRNA and evaluated their efficacy in several tumor-derived cells, including the A431 cell line, that express amplified levels of EGFr. A 15-mer phosphorothioate (PS) antisense ODN (erbB1AS15) induced a concentration-dependent reduction in proliferation that was accompanied by a change in the morphology of A431 cells into more tightly clustered and discrete colonies. A 15-mer sense (PS) control oligodeoxynucleotide (ODN) and a phosphodiester (PO) version of erbB1AS15 had little or no effect on cell number of morphology, and erbB1AS15 (PS) did not induce these effects in control cell lines expressing lower levels of EGFr. The effects of erbB1AS15 (PS) on A431 cells were not mediated by a true antisense mechanism in that there was no reduction in the level of EGFr mRNA or protein over a 24-hr period, as determined by Northern and Western blotting, respectively. However, autophosphorylation of the receptor was significantly reduced by erbB1AS15 (PS) and not by control ODNs. The results of further studies suggested that this effect was mediated by a direct, dose-dependent inhibition of the EGFr tyrosine kinase enzyme and was not due to impairment of either ligand-binding or receptor dimerization. These data suggest that erbB1AS15 (PS) can inhibit proliferation and alter the morphology of A431 cells by a sequence-selective, but nonantisense, mechanism affecting receptor tyrosine kinase activity.
Mol Pharmacol 1996 Aug
PMID:A nonantisense sequence-selective effect of a phosphorothioate oligodeoxynucleotide directed against the epidermal growth factor receptor in A431 cells. 870 Jan 39

A differential polymerase chain reaction (PCR) protocol was established for semiquantitative, nonradioactive detection of gene amplification using a DNA sequencer. Oncogene fragments and control DNA sequences were simultaneously PCR-amplified using fluorescent-labelled primers. Analysis of the PCR products allowed quantitative assessment of gene copy numbers in this coamplification assay. Using this approach, we examined a series of 132 brain tumors for amplification of the epidermal growth factor receptor (EGFR) gene. The same set of tumors was also analyzed by Southern blotting and hybridization with a radiolabelled EGFR probe. Both methods yielded virtually identical results. This technique has a great potential for nonradioactive screening of large tumor panels of oncogene amplification.
Diagn Mol Pathol 1996 Jun
PMID:A polymerase chain reaction-based assay for the rapid detection of gene amplification in human tumors. 872 2

The genetic and phenotypic properties of cells which ultimately give rise to carcinoma of the lung are not well defined in part because of unavailability of preneoplastic cells from well-characterized dysplastic sites. In order to expand bronchial epithelial cell populations from patients at high risk for lung cancer, endobronchial biopsy specimens were explanted onto collagen- and fibronectin-coated dishes and cultured in serum-free, chemically defined media. One hundred forty-nine biopsy pairs were obtained from smokers and from healthy volunteers for culture and histologic evaluation. The histologic appearances of mucosa adjacent to the site of the cultured biopsies ranged from normal through varying degrees of noninvasive squamous dysplasia to invasive carcinoma. Confluent monolayers of pure epithelial cells were obtained from 68% of the cultured explants. Sites exhibiting high-grade dysplasia were 51% more likely to yield successful cultures than sites exhibiting normal histology (13 of 14 cultures successful versus 52 of 83 cultures successful, P < 0.02). Cultures had a maximum proliferative life span of 81 days and none of the cultures spontaneously became immortalized. Immunolabeling studies revealed that all cultured epithelial cells, regardless of the in situ histologic appearances of the mucosa at the biopsy site, strongly expressed keratin and epidermal growth factor receptor, weakly expressed transferrin receptor and human folate receptor, and were negative for neural cell adhesion molecule and human leukocyte antigen DR (HLADR). Ploidy and karyotypic analyses were performed in a limited number of explants from normal and dysplastic sites and all were found to be diploid without karyotypic abnormality. We conclude that pure bronchial epithelial cell populations can be routinely expanded from histologically normal and dysplastic sites by tissue culture of biopsy explants and that the expanded cell populations may represent a library of normal and preneoplastic cells which are suitable for immunophenotypic, ploidy, genetic, or functional analyses.
Am J Respir Cell Mol Biol 1996 Sep
PMID:Expansion of bronchial epithelial cell populations by in vitro culture of explants from dysplastic and histologically normal sites. 881 Jun 33


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