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Query: UNIPROT:P06889 (Mol)
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We used targeted homologous recombination to disrupt one c-myc gene copy in a diploid fibroblast cell line and found that a twofold reduction in Myc expression resulted in lower exponential growth rates and a lengthening of the G0-to-S-phase transition (M. Shichiri, K. D. Hanson and J. M. Sedivy, Cell Growth Differ. 4:93-104, 1993). Myc is a transcription factor, and the number of target genes whose regulation could result in differential growth rates may be very large. We have approached this problem by examining effects of reduced c-myc expression in three broad areas: (i) secretion of growth factors, (ii) expression of growth factor receptors, and (iii) intracellular signal transduction between Myc and components of the intrinsic cell cycle clock. We have found no evidence that differential medium conditioning can account for the growth phenotypes. Likewise, the expression of receptors for platelet-derived growth factor, epidermal growth factor, basic fibroblast growth factor, and insulin-like growth factor I was the same in diploid and heterozygous cells (platelet-derived growth factor, epidermal growth factor, fibroblast growth factor, and insulin-like growth factor are the sole growth factors required by these cells for growth in serum-free medium). In contrast, expression of cyclin E, cyclin A, and Rb phosphorylation were delayed when quiescent c-myc heterozygous cells were stimulated to enter the cell cycle. Expression of cyclin D1, cyclin D3, and Cdk2 was not affected. The timing of cyclin E induction was the earliest observable effect of reduced Myc expression. Our data indicate that Myc contributes to regulation of proliferation by a cell-autonomous mechanism that involves the modulation of cyclin E expression and, consequently, progression through the restriction point of the cell cycle.
Mol Cell Biol 1994 Sep
PMID:Effects of c-myc expression on cell cycle progression. 806 9

We have shown that the insulin-like growth factor type I and II receptors are expressed equally from the maternal and paternal alleles in human tissues. The imprinting status of the type I insulin-like growth factor receptor has not been reported while the type II receptor has previously been shown to be maternally expressed in the mouse. That the imprinting of the insulin-like growth factor type II receptor is not conserved between mouse and humans suggests that the physiological role of the IGF2 receptor may differ between these two species.
Hum Mol Genet 1993 Dec
PMID:Human insulin-like growth factor type I and type II receptors are not imprinted. 811 87

We have established a novel granulosa cell line derived from porcine ovarian follicles (4-6 mm in diameter). This cell line, MDG2.1, was obtained by transfection of freshly cultured cells with the plasmid pSV3neo. Doubling time for MDG2.1 cells is 24-36 h. Northern analysis for RNAs of the insulin-like growth factor (IGF) regulatory system indicates that RNAs for IGF-I, IGF-I receptor, and IGF binding proteins (IGFBP) 2-6, but not IGFBP-1, are expressed in MDG2.1 cells. The secretion of IGFBPs from MDG2.1 cells shows > 10-fold levels of the 24 kDa form, reduced secretion of other IGFBPs, with no change in the total amount of IGFBP secreted, as compared to primary cells cultured under identical conditions. Use of endoglycosidase F indicated that several IGFBPs are posttranslationally modified. This cell line is a useful model and plasmid transfection target system to investigate IGFBP action in ovarian granulosa cells.
Mol Cell Endocrinol 1993 Nov
PMID:Expression of the IGF system in primary and immortalized porcine ovarian granulosa cells. 814 3

Reexpression of the insulin-like growth factor type II (IGF-II) gene has recently been described in hepatocellular carcinoma (HCC). In this study, we used a nonisotopic in situ hybridization method to analyze the expression of IGF-II mRNA in a series of 28 HCCs arising on cirrhotic and noncirrhotic livers. An immunohistochemical method was used to detect IGF-II peptide. Hepatitis B virus (HBV) status and the histological differentiation degree were also evaluated. Increased expression of IGF-II mRNA was found in 4 of 28 HCCs, and 7 of 17 cirrhotic patients showed IGF-II mRNA in the cirrhotic nodules surrounding the HCC. A slightly higher rate of positivity for IGF-II mRNA was found in the HBV-negative patients than in HBV-positive ones. Positive immunostaining for the IGF-II peptide in the HCC and/or in surrounding cirrhotic nodules was found in 10 of 28 cases. The normal hepatocytes of the noncirrhotic patients were always negative for IGF-II peptide and mRNA. The similarities between our results and those from experimental models in woodchucks seem to support the concept that heterogeneous phenotypic groups could exist in human HCCs.
Diagn Mol Pathol 1994 Mar
PMID:Different in situ expression of insulin-like growth factor type II in hepatocellular carcinoma. An in situ hybridization and immunohistochemical study. 816 57

In the absence of serum and estrogen, we show that the growth of the prolactin secreting pituitary tumour cell line, GH3 is stimulated by insulin and insulin-like growth factor-1 (IGF-1) and this response is blocked by the steroidal antiestrogens, ICI 164384 and ICI 182780. From conditioned medium (CM) experiments, growth of low density cells (10k/cm2) is increased by the addition of CM from high density cells (100k/cm2) and this growth effect is also blocked by antiestrogen. Transfection studies with a delta MTV-ERE-LUC reporter plasmid show that in the absence of estrogen and serum, both insulin and IGF-1 induce luciferase expression and this is blocked by the pure antiestrogens. No effect of these treatments was apparent when parallel experiments were conducted with a plasmid construct lacking the vitellogenin estrogen response element. From these and other data discussed in this report, we conclude that for GH3 cells, in the absence of estrogen and serum, the ER is transcriptionally activated by intracellular peptide factor pathways and by this means, acts as the key nuclear factor inducing mitogenesis in response to autocrine and exogenously added growth factors.
J Steroid Biochem Mol Biol 1994 Apr
PMID:The unliganded estrogen receptor (ER) transduces growth factor signals. 818 Jan 9

Fibroblast cell lines, designated R- and W cells, were generated, respectively, from mouse embryos homozygous for a targeted disruption of the Igf1r gene, encoding the type 1 insulin-like growth factor receptor, and from their wild-type littermates. W cells grow normally in serum-free medium supplemented with various combinations of purified growth factors, while pre- and postcrisis R- cells cannot grow, as they are arrested before entering the S phase. R- cells are able to grow in 10% serum, albeit more slowly than W cells, and with all phases of the cell cycle being elongated. An activated Ha-ras expressed from a stably transfected plasmid is unable to overcome the inability of R- cells to grow in serum-free medium supplemented with purified clones. Nevertheless, even in the presence of serum, R- cells stably transfected with Ha-ras, alone or in combination with simian virus 40 large T antigen, fail to form colonies in soft agar. Reintroduction into R- cells (or their derivatives) of a plasmid expressing the human insulin-like growth factor I receptor RNA and protein restores their ability to grow with purified growth factors or in soft agar. The signaling pathways participating in cell growth and transformation are discussed on the basis of these results.
Mol Cell Biol 1994 Jun
PMID:Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts. 819 6

In human fibroblasts, exogenous insulin-like growth factor-II (IGF-II) induce a rapid redistribution of mannose 6-phosphate/IGF-II receptors. To analyze the mechanism transducing the IGF-II signal the phosphoinositide hydrolysis, 1,2-diacyglycerol and cAMP formation were studied after incubation with IGFs. While IGF-I (10 nM, 30 s) increased the inositol trisphosphate formation IGF-II (10 nM, up to 10 min) failed to affect phosphoinositide hydrolysis and had neither an effect on basal concentrations of diacylglycerol containing arachidonic acid or myristic acid nor on intracellular cAMP. On the contrary, pretreatment with IGF-II for 10 min enhanced the cAMP production stimulated by bradykinin (10 nM, 3 min) by 2.5-fold whereas no additive effects of IGF-II on the increased ligand binding to the mannose 6-phosphate/IGF-II receptor in response to bradykinin were observed. These results indicate that in fibroblasts the rapid IGF-II-induced redistribution of mannose 6-phosphate/IGF-II receptors is not mediated by inositol trisphosphate, diacylglycerol or cAMP, but that IGF-II may modulate permissively other agonist-generated signals.
Mol Cell Endocrinol 1994 Mar
PMID:Effects of insulin-like growth factor II on the generation of inositol trisphosphate, diacylglycerol and cAMP in human fibroblasts. 820 19

We have investigated the possibility that some serum factors might negatively regulate the expression of the insulin-like growth factor-II (IGF-II) gene in 18-54, SF cells. Northern blot analyses indicated that there were three major transcripts (3.8 kb, 1.8 kb, and 1.2 kb) of the IGF-II gene in these cells. We found that incubation of 18-54, SF cells in medium containing very high concentrations (50-100%) of chicken serum greatly inhibited the steady-state level of all three IGF-II mRNA species. In addition, we also found that incubation of 18-54, SF cells in medium containing lower concentrations (10-50%) of chicken serum induced a 3.5 kb IGF-II mRNA. The inhibitory effect of high concentrations of chicken serum on IGF-II mRNA expression was not due to a cytotoxic effect of the serum, because these cells were maintained in 100% chicken serum for up to two weeks without loss of cell viability. The inhibitory effect of chicken serum on IGF-II mRNA was reversible after withdrawal of the serum. Nuclear run-on assays suggested that this negative regulation of IGF-II mRNA in 18-54, SF cells by chicken serum was not the result of transcriptional inhibition. Treatment of 18-54, SF cells that had been previously incubated in 100% chicken serum for 24 h with actinomycin D resulted in a partial restoration of the expression of the 3.8 kb and 1.2 kb IGF-II mRNA in these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1994 Mar
PMID:Negative and positive regulation of IGF-II mRNA expression in cultured rat cells by chicken serum. 820 36

We have previously shown that lactogenic hormones stimulate epidermal growth factor (EGF) mRNA accumulation in mouse mammary glands in vivo and in mouse mammary epithelial cells (NMuMG line). However, our in vitro studies indicate that the lactogenic hormone prolactin (PRL) completely inhibits EGF-stimulated DNA synthesis. PRL does not alter cholera toxin or insulin-like growth factor-1-stimulated cell growth, thus the inhibition appears to be specific for EGF. Our current studies are designed to evaluate the effects of PRL on EGF-stimulated signaling events in the NMuMG cell line. Cells treated with PRL for 30 min demonstrated a loss of high affinity EGF-binding ability. After long-term PRL treatment (18 h) there was a decrease in EGF receptor (R) number, as determined by [125I]EGF binding. PRL treatment (8 h) also decreased EGF-R mRNA levels. An EGF-stimulated increase in EGF-R mRNA observed 2-4 h after treatment was decreased when PRL was added to the cultures. Furthermore, levels of EGF-stimulated tyrosine phosphorylation of the EGF-R (170 kDa) and phospholipase C gamma (145 kDa) are dramatically decreased in cells treated with PRL. Also of great interest was a decrease in EGF-stimulated c-myc mRNA in PRL-treated cells. We conclude that PRL is acting to down-regulate the EGF-R, thus limiting EGF-stimulated cell signaling in mammary tissue.
Mol Biol Cell 1993 Aug
PMID:Prolactin inhibits epidermal growth factor (EGF)-stimulated signaling events in mouse mammary epithelial cells by altering EGF receptor function. 824 65

The mRNA levels for aminolevulinate synthase (ALV-S), the rate-limiting enzyme in porphyrin synthesis, were studied in male and female Syrian hamsters during postnatal development. Sex-associated differences in the expression of ALV-S gene were evident at the end of the third week of postnatal development. Serum levels of luteinizing hormone (LH), testosterone, cortisol, thyroid hormones and insulin-like growth factor were also studied in order to correlate their concentrations with the mRNA levels for ALV-S. Among these hormones, serum LH levels showed a positive correlation with the ALV-S mRNA levels. However, the expected negative correlation with testosterone levels was not clearly observed. Thus, in order to test the effects of testosterone on ALV-S gene expression, 11-day-old male and female Syrian hamsters and adult female hamsters were injected with 50 micrograms of testosterone for 4 days. Testosterone administration decreased the levels of ALV-S mRNA in the adult females but did not influence those of young females. The possible explanation for the insensitivity to testosterone during these postnatal stages might involve the maturational state of androgen receptors in the Harderian glands.
Mol Cell Endocrinol 1993 Jun
PMID:Gender-associated differences in the development of 5-aminolevulinate synthase gene expression in the harderian gland of Syrian hamsters. 834 26


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