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Query: UNIPROT:P06889 (Mol)
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Previous studies have demonstrated that the mouse c-Harvey ras proto-oncogene (c-Ha-ras) promoter sequences are GC rich and contain several potential transcription factor SP1 binding sites. We investigated the endonuclease hypersensitivity of this region in nuclei in vitro and whole mouse tissues in vivo and identified a very strong, ubiquitous hypersensitive site covering the proximal promoter sequences. Footprint protection studies using nuclear extracts from various cell types including fibroblasts, erythroid cells, and both normal and transformed epithelial cells revealed a consistent protein-binding pattern. Five protein binding sites were observed, four of which correlated with potential SP1 binding sites. Competition experiments using an oligonucleotide corresponding to a consensus SP1 binding site confirmed that these sequences were indeed bound by the SP1 (or SP1-like) trans-acting factor. In addition, no differences were observed between the footprint patterns obtained using extracts from cells of different lineages or between normal and transformed epithelial cells carrying activated ras genes. The controlling elements responsible for differential c-Ha-ras transcription between cell types or at different stages of carcinogenesis therefore probably lie in other regions of the gene.
Mol Carcinog 1991
PMID:Structural analysis of the mouse c-Ha-ras gene promoter. 204 51

Transcription of the proto-oncogene c-fos is known to be activated by growth factors in serum and subsequently repressed by the Fos protein. We show that generalized DNase I sensitivity of c-fos chromatin correlates closely with enhancer activity during induction, repression, and superinduction of the c-fos gene. Within 90 s of serum stimulation, proximal DNA sequences on both sides of the enhancer exhibit increased DNase I sensitivity. Within 5 min, elevated DNase I sensitivity spreads to chromatin at the distal 3' end of the c-fos gene. These results suggest that an open state of chromatin is propagated in both directions from the enhancer. The induced alterations in chromatin structure precede the increased transcriptional activity of the c-fos gene, suggesting that these changes in chromatin structure potentiate transcription.
Mol Cell Biol 1990 Mar
PMID:Serum stimulation of the c-fos enhancer induces reversible changes in c-fos chromatin structure. 210 68

The mechanism by which the products of the v-rel oncogene, the corresponding c-rel proto-oncogene, and the related dorsal gene of Drosophila melanogaster exert their effects is not clear. Here we show that the v-rel, chicken c-rel, and dorsal proteins activated gene expression when fused to LexA sequences and bound to DNA upstream of target genes in Saccharomyces cerevisiae. We have defined two distinct activation regions in the c-rel protein. Region I, located in the amino-terminal half of rel and dorsal proteins, contains no stretches of glutamines, prolines, or acidic amino acids and therefore may be a novel activation domain. Lesions in the v-rel protein that diminished or abolished oncogenic transformation of avian spleen cells correspondingly affected transcription activation by region I. Region II, located in the carboxy terminus of the c-rel protein, is highly acidic. Region II is not present in the v-rel protein or in a transforming mutant derivative of the c-rel protein. Our results show that the oncogenicity of Rel proteins requires activation region I and suggest that the biological function of rel and dorsal proteins depends on transcription activation by this region.
Mol Cell Biol 1990 Jun
PMID:Oncogenic transformation by vrel requires an amino-terminal activation domain. 211 43

A 2.4-kb rat neu genomic DNA fragment that hybridized to the 5'-most coding sequence of the rat neu cDNA was cloned. S1 nuclease mapping identified multiple transcriptional initiation sites. DNA sequence analysis revealed that this fragment contained 64 bp of the first intron, 81 bp of the first exon, and the upstream noncoding sequence of the neu gene. The sequence immediately upstream of the translation start site was G + C rich (greater than 75%) and contained a consensus CCAAT sequence despite the absence of a TATA box. An Sp1-binding site was found, in addition to various sequence motifs common to the promoters of the human neu gene (erbB2), the epidermal growth factor receptor gene, and the simian virus 40 enhancer. A 2.2-kb EcoRI-Narl fragment containing sequences upstream from the 3'-most transcriptional start site was fused to the bacterial chloramphenicol acetyltransferase reporter gene and shown to promote transcription efficiently. A series of promoter deletion constructs was made, and results from transfection and subsequent chloramphenicol acetyltransferase assays suggested the presence of multiple cis-acting elements that contributed either positively or negatively to the transcription activity. Cotransfection competition experiments using subcloned cis-acting elements confirmed the existence of trans-acting factors interacting with these DNA fragments. In addition, a gel retardation assay was performed to demonstrate the physical binding of nuclear factors to certain fragments. The results complemented those of the deletion studies and led us to conclude that transcriptional regulation of the neu proto-oncogene involves at least one negative and three positive trans-acting factors interacting with different cis-acting elements along the neu gene promoter.
Mol Cell Biol 1990 Dec
PMID:Multiple cis- and trans-acting elements involved in regulation of the neu gene. 212 92

Approximately one third of the human breast tumors are estradiol (E2)-dependent in the initial stages of the disease. E2 is thought to stimulate growth indirectly, through induced production of autocrine polypeptide growth factors. In this hypothesis constitutive production of such growth factors would lead to the loss of E2 dependence, as associated with progression of the disease. Recent data, however, suggest that breast cancer cells do not react to the growth factors that they produce. Here we provide evidence that the direct stimulation of the c-fos proto-oncogene may be an important step in the stimulation by E2 of the human breast cancer cell line MCF7. E2 by itself, however, is poorly mitogenic, and it does not induce genes from the jun family, whose gene products are necessary for heterodimerization with the c-fos-encoded protein (Fos), leading to an important step in growth factor signalling pathways, stimulation of TPA-responsive element (TRE)-dependent transcriptional activity. In combination with insulin-like growth factors, that were found to be efficient inducers of c-jun in breast cancer cells, E2 synergistically stimulates TRE activity and proliferation. These effects of E2 on growth factor signalling pathways indicate that E2 may directly induce the proliferation of MCF7 cells, independent from autocrine growth factors.
Mol Endocrinol 1990 Nov
PMID:Stimulation of TPA-responsive element activity by a cooperative action of insulin and estrogen in human breast cancer cells. 212 40

The proto-oncogene product pp60c-src is a tyrosine-specific kinase with a still unresolved cellular function. High levels of pp60c-src in neurons and the existence of a neuronal pp60c-src variant, pp60c-srcN, suggest participation in the progress or maintenance of the differentiated phenotype of neurons. We have previously reported that phorbol esters, e.g., 12-O-tetradecanoylphorbol-13-acetate (TPA), stimulate human SH-SY5Y neuroblastoma cells to neuronal differentiation, as monitored by morphological, biochemical, and functional differentiation markers. In this report, we describe activation of the pp60src (pp60c-src and pp60c-srcN) kinase activity observed at 6 h after induction of SH-SY5Y cells with TPA. This phenomenon coincides in time with neurite outgrowth, formation of growth cone-like structures, and an increase of GAP43 mRNA expression, which are the earliest indications of neuronal differentiation in these cells. The highest specific src kinase activity (a three- to fourfold increase 4 days after induction) was noted in cells treated with 16 nM TPA; this concentration is optimal for development of the TPA-induced neuronal phenotype. During differentiation, there was no alteration in the 1:1 ratio of pp60c-src to pp60c-srcN found in untreated SH-SY5Y cells. V8 protease and trypsin phosphopeptide mapping of pp60src from in vivo 32P-labeled cells showed that the overall phosphorylation of pp60src was higher in differentiated than in untreated cells, mainly because of an intense serine 12 phosphorylation. Tyrosine 416 phosphorylation was not detectable in either cell type, and no change during differentiation in tyrosine 527 phosphorylation was observed.
Mol Cell Biol 1990 Jan
PMID:Early activation of endogenous pp60src kinase activity during neuronal differentiation of cultured human neuroblastoma cells. 213 66

The murine int-1 proto-oncogene has been implicated in neural development and, when transcriptionally activated by mouse mammary tumor virus, contributes to the genesis of mammary tumors. To understand the function of the int-1 gene product in these processes, we have characterized the biochemical properties of int-1 protein expressed in a neuroendocrine cell line transfected with int-1 cDNA. Here we provide evidence that int-1 protein is secreted and associates with the cell surface. int-1 protein was very efficiently processed and secreted through the constitutive secretory pathway, although no int-1 protein could be immunoprecipitated from the culture medium. Treatment with suramin effectively released mature int-1 proteins into the culture fluid, which suggests that secreted int-1 protein associates with the cell surface or extracellular matrix. We have also shown directly, by radioiodination of intact cells and by surface antibody adsorption, that secreted int-1 proteins can be detected on the cell surface. These data support a model in which int-1 protein is secreted and functions locally in cell-to-cell signaling.
Mol Cell Biol 1990 Jun
PMID:Secreted int-1 protein is associated with the cell surface. 214 Apr 30

We investigated the biological effects of sex-steroid hormones, secreted from the corpus luteum and placenta, on the induction of mRNAs encoding macrophage colony-stimulating factor (MCSF) and c-fms proto-oncogene (MCSF receptor) in human endometrium. RNA was extracted from the placenta and endometrium of both pregnant and non-pregnant women, and Northern blot analysis was performed on poly(A)+ RNA using MCSF or c-fms proto-oncogene cDNA as the probe. Results showed: (1) that MCSF mRNA was expressed in the placenta and endometrium of the pregnant uterus, (2) that c-fms proto-oncogene mRNA was also expressed in the placenta and endometrium of the pregnant uterus, and (3) that exogenous sex-steroid hormones could induce the expression of MCSF and c-fms proto-oncogene mRNAs in the endometrium of non-pregnant women. These results indicate that sex-steroid hormones secreted by the corpus luteum and/or placenta influence endometrial and placental growth and differentiation via a mechanism of action involving local production of MCSF and its receptor.
J Mol Endocrinol 1990 Oct
PMID:Steroid hormones induce macrophage colony-stimulating factor (MCSF) and MCSF receptor mRNAs in the human endometrium. 214 74

Treatment with insulin or progesterone or microinjection of the transforming protein product of Ha-rasVal-12,Thr-59 (p21) is known to induce germinal vesicle breakdown in Xenopus oocytes. We have investigated the effect of p21 on S6 kinase and the H1 histone kinase of maturation-promoting factor in the presence and absence of antisense oligonucleotides against the c-mosxe proto-oncogene. Injection of p21 led to a rapid increase in S6 phosphorylation, with kinetics similar to those previously observed with insulin. Microinjection of c-mosxe antisense oligonucleotides inhibited germinal vesicle breakdown induced by p21 and totally abolished S6 kinase activation by insulin or progesterone but only partially inhibited activation by p21. However, the activation of p34cdc2 protein kinase by all three stimuli was blocked by antisense oligonucleotides. The results suggest that in oocyte maturation c-mosxe functions downstream of p21 but upstream of p34cdc2 and S6 kinase activation, although not all p21-induced events require c-mosxe.
Mol Cell Biol 1990 Jan
PMID:Ha-rasVal-12,Thr-59 activates S6 kinase and p34cdc2 kinase in Xenopus oocytes: evidence for c-mosxe-dependent and -independent pathways. 215 63

Fos, the product of the proto-oncogene c-fos, is a nuclear phosphoprotein thought to participate in transcriptional regulation of target genes. To explore the synaptic induction of Fos and related proteins in vivo, Fos immunohistochemistry was performed in the rabbit retina. Dark-adapted retinas had virtually no Fos immunostaining. Retinas of dark-adapted rabbits that were exposed to 3 Hz diffuse flashing white light for 1 h and sacrificed 2 h later displayed nuclear Fos immunostaining in a minority of neurons. These included presumptive amacrine cells of the inner nuclear layer and either displaced amacrine cells or ganglion cells of the ganglion cells of the ganglion cell layer. Therefore, Fos or a related antigen is expressed in a subset of retinal neurons in response to light and is presumably involved in regulating gene expression of these cells to respond to alterations in synaptic activity.
Brain Res Mol Brain Res 1990 Jan
PMID:Light induces a Fos-like nuclear antigen in retinal neurons. 215 91


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