Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The c-fos proto-oncogene mRNA is rapidly degraded within minutes after its appearance in the cytoplasm of growth factor-stimulated mammalian fibroblasts. At least two functionally independent sequence elements are responsible for the lability of c-fos mRNA. One of these determinants is located within a 0.32-kb sequence present in the protein-coding region. We demonstrate by gel mobility shift experiments and UV cross-linking that at least two protein factors specifically interact with a 56-nucleotide purine-rich sequence located at the 5' end of the 0.32-kb coding region determinant of mRNA instability (CRDI). One protein is predominantly associated with the polysomes, while the other is detected in the post-ribosomal supernatant. Sequence comparison of members of the fos gene family revealed that the high purine content of the protein-binding region is conserved through evolution. Deletion of this region from the 0.32-kb CRDI severely impedes its function as an RNA-destabilizing element. Our results suggest that binding of the two proteins to the purine-rich sequence may participate in the rapid mRNA decay mediated by this 0.32-kb c-fos CRDI.
Mol Cell Biol 1992 Dec
PMID:Two cellular proteins bind specifically to a purine-rich sequence necessary for the destabilization function of a c-fos protein-coding region determinant of mRNA instability. 144 2

Following activation with the inflammatory mediator phorbol myristate acetate (PMA), human microvascular endothelial cells (DMEC) is olated from the human dermis (DMEC) rapidly and dramatically convert from a classical epithelioid morphology to a spindle-shaped configuration. This is accompanied by changes in the organization of gap junctions and the vimentin and actin cytoskeletons. This report describes the sequential changes in the expression of four proto-oncogenes, c-fos, c-myc, c-sis and H-ras in DMEC following PMA exposure. The synthesis of c-fos mRNA was transiently induced by PMA from a basal concentration below the limit of detection to a maximum at 60 min., declining to the unstimulated level within 2 hrs. Synthesis of c-myc mRNA declined continuously and reached 37% of control levels over 16 hrs. Expression of c-sis which encodes for the B chain of platelet-derived growth factor, also declined to 34% of the control value over 16 hrs. There was no change in the synthesis of H-ras mRNA nor of beta-actin mRNA which was used as a control. The expression of c-myc in normal DMEC was compared to a human dermal microvascular cell line transformed by SV-40 (TREND). The TREND cell line maintains a permanent spindle-shaped configuration under all growth conditions and multiplies faster than DMEC. In contrast to the non-transformed cell cultures, expression of c-myc in TREND cells was induced by PMA.(ABSTRACT TRUNCATED AT 250 WORDS)
Cell Mol Biol (Noisy-le-grand) 1992 Nov
PMID:Modification of proto-oncogene expression by phorbol esters in human dermal microvascular endothelial cells. 147 5

PTH is a potent regulator of osteoblast gene expression, yet the nuclear events that mediate PTH action are poorly understood. We were interested in identifying immediate early genes which may regulate PTH-altered gene expression in the osteoblast. Therefore, we examined the effects of PTH on c-fos and c-jun gene expression in a rat osteoblastic cell line (UMR 106-01). Under control conditions, c-fos and c-jun mRNAs were present at low basal levels. After PTH treatment, c-fos mRNA abundance dramatically increased, with a maximal and transient response at 30 min. PTH also stimulated an increase in c-jun mRNA, but in a biphasic manner, with maximal levels at 30 min and 2 h. These responses were dose dependent, not altered by cotreatment with the protein synthesis inhibitor cycloheximide, and preceded PTH-induced expression of matrix metallo-proteinase-1 mRNA. Nuclear run-on assays demonstrated an increased rate of c-fos and c-jun transcription after PTH exposure. To determine the signal transduction pathways involved, second messenger analogs were tested for their ability to mimic the effects of PTH. 8-Bromo-cAMP and phorbol 12-myristate 13-acetate (PMA) caused increases in the abundance of c-fos and c-jun transcripts. Ionomycin had no effect on the expression of these genes. Pretreatment of the cells with PMA resulted in a decrease in basal c-jun expression, but did not alter the PTH-mediated increase in c-fos, c-jun, or matrix metalloproteinase-1 mRNAs.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1992 Nov
PMID:Parathyroid hormone induces c-fos and c-jun messenger RNA in rat osteoblastic cells. 148 Jan 73

Testicular peritubular cells produce a paracrine factor, PModS, under androgen control that modulates Sertoli cell functions that are essential for the process of spermatogenesis. PModS has a more dramatic effect on Sertoli cell differentiated functions in vitro than any regulatory agent previously shown to influence the cell, including FSH. Investigation of the actions of PModS on a molecular level have used transferrin expression as a marker of Sertoli cell differentiation. PModS was found to stimulate transferrin gene expression while having no effect on transferrin mRNA stability. The ability of PModS to elevate transferrin mRNA levels was inhibited by cycloheximide. Therefore, the actions of PModS require ongoing protein synthesis and appear to be indirectly mediated through trans-acting early event genes. PModS was found to dramatically increase mRNA levels for c-fos, but had no effect on c-jun mRNA levels. The c-fos mRNA levels increased transiently within a few minutes to a maximal level of stimulation at 1 h and returned to basal levels within 6 h. The rise in c-fos mRNA preceded the elevation in transferrin mRNA, which started to increase at 2 h to a maximum level between 6-12 h that was maintained at high levels for several days in cell culture. Treatment of Sertoli cells with an antisense c-fos oligonucleotide was found to inhibit the actions of PModS on transferrin expression. Combined results support the hypothesis that PModS acts indirectly through transcription factors (e.g. c-fos) to induce Sertoli cell differentiated functions (e.g. transferrin expression). Therefore, PModS appears to act as a differentiation-type factor to promote and maintain optimal Sertoli cell function.
Mol Endocrinol 1992 Dec
PMID:Regulation of Sertoli cell differentiation by the testicular paracrine factor PModS: potential role of immediate-early genes. 149 88

Mammary epithelial cells terminally differentiate in response to lactogenic hormones. We present evidence that oncoprotein overexpression is incompatible with this hormone-inducible differentiation and results in striking cellular morphological changes. In mammary epithelial cells in culture, lactogenic hormones (glucocorticoid and prolactin) activated a transfected beta-casein promoter and endogenous beta-casein gene expression. This response to lactogenic hormone treatment was paralleled by a decrease in cellular AP-1 DNA-binding activity. Expression of the mos, ras, or src (but not myc) oncogene blocked the activation of the beta-casein promoter induced by the lactogenic hormones and was associated with the maintenance of high levels of AP-1. Mos expression also increased c-fos and c-jun mRNA levels. Overexpression of Fos and Jun from transiently transfected constructs resulted in a functional inhibition of the glucocorticoid receptor in these mouse mammary epithelial cells. This finding clearly suggests that glucocorticoid receptor inhibition arising from oncogene expression will contribute to the block in hormonally induced mammary epithelial cell differentiation. Expression of Src resulted in the loss of the normal organization and morphological phenotype of mammary epithelial cells in the epithelial/fibroblastic line IM-2. Activation of a conditional c-fos/estrogen receptor gene encoding an estrogen-dependent Fos/estrogen receptor fusion protein also morphologically transformed mammary epithelial cells and inhibited initiation of mammary epithelial differentiation-associated expression of the beta-casein and WDNM 1 genes. In response to estrogen treatment, the cells displayed a high level of AP-1 DNA-binding activity. Our results demonstrate that high cellular AP-1 levels contribute to blocking the ability of mammary epithelial cells in culture to respond to lactogenic hormones. This and other studies indicate that the oncogene products Mos, Ras, and Src exert their effects, at least in part, by stimulating cellular Fos and probably cellular Jun activity.
Mol Cell Biol 1992 Sep
PMID:Overexpression of Mos, Ras, Src, and Fos inhibits mouse mammary epithelial cell differentiation. 150 91

The rapid, transient induction of the c-fos proto-oncogene by serum growth factors is mediated by the serum response element (SRE). The SRE shares homology with the muscle regulatory element (MRE) of the skeletal alpha-actin promoter. It is not known how these elements respond to proliferative and cell-type-specific signals, but the response appears to involve the binding of the serum response factor (SRF) and other proteins. Here, we report that YY1, a multifunctional transcription factor, binds to SRE and MRE sequences in vitro. The methylation interference footprint of YY1 overlaps with that of the SRF, and YY1 competes with the SRF for binding to these DNA elements. Overexpression of YY1 repressed serum-inducible and basal expression from the c-fos promoter and repressed basal expression from the skeletal alpha-actin promoter. YY1 also repressed expression from the individual SRE and MRE sequences upstream from a TATA element. Unlike that of YY1, SRF overexpression alone did not influence the transcriptional activity of the target sequence, but SRF overexpression could reverse YY1-mediated trans repression. These data suggest that YY1 and the SRF have antagonistic functions in vivo.
Mol Cell Biol 1992 Sep
PMID:Functional antagonism between YY1 and the serum response factor. 150 14

The 21-amino acid mammalian peptide endothelin (ET) is a powerful vasoconstrictor, a mitogen for fibroblasts and vascular smooth muscle cells, and a potent effector for numerous tissues. Through extracellular interaction with G protein-coupled transmembrane receptors, ET stimulates intracellular second messenger events that in turn activate immediate early gene transcription. Using Northern blot hybridization and nuclear run-on analyses, we examined the modulation of c-fos, fos-B, fra-1, c-jun, and jun-B gene transcripts in Rat-1 fibroblasts after ET treatment. Furthermore, we investigated the role that intracellular Ca2+ transients played in effecting this gene regulation, using the intracellular Ca2+ chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) to block Ca(2+)-dependent transcription. Our results demonstrate that ET rapidly effects increased RNA levels for all five fos/jun family genes investigated, at least two of them by increasing gene transcription. Furthermore, our results argue that increased intracellular free Ca2+ is directly involved in the induction of these fos/jun family genes by ET. While mobilization of intracellular Ca2+ is not the only pathway to fos/jun gene induction used by ET, it is clearly a major component of the signaling apparatus that is set in motion by this potent effector.
Mol Endocrinol 1992 Jul
PMID:Endothelin induces transcription of fos/jun family genes: a prominent role for calcium ion. 150 17

Structural heterogeneity has been demonstrated for growth hormone (GH) receptors from a number of species, and both high and low affinity art receptors have been characterised by ligand binding studies. In the present study, we have transfected Chinese hamster ovary (CHO-K1) cells with a cDNA clone encoding a full-length transmembrane ovine (o) GH receptor, under the regulatory control of the human metallothionein IIA promoter. A stably transfected cell line was established (GHR9.5) which expresses on the cell surface a single class of receptor which binds 220,000 [125I]oGH molecules at high affinity (Kd = 0.30 nM) which is comparable to the affinity established for endogenous oGH receptors in postnatal sheep liver microsomes (Kd = 0.27 nM, Freemark et al. (1987) Endocrinology 120, 1865-1872). The expressed receptor also binds ovine placental lactogen (oPL, 205,000 binding sites per cell) with high affinity (Kd = 0.76 nM). The presence of two species of oGH receptor was detected in GHR9.5 cells using affinity cross-linking analysis (M(r) 148,000 and M(r) 73,000) and given that the oGH receptor cDNA codes for a non-glycosylated receptor of M(r) 69,914, it is likely that these cross-linked species correspond to homodimeric and monomeric forms of the oGH receptor, each binding to a single molecule of GH. Parallel cross-linking studies with sheep liver microsomes also demonstrated two oGH receptor species (M(r) 133,000 and M(r) 58,000), the difference in relative molecular weights between the transfected and endogenous receptors presumably resulting from tissue-specific post-translational modifications. In the presence of oGH, the GHR9.5 cells respond by increasing total cellular protein synthesis by 27% relative to non-GH-exposed GHR9.5 cells, indicating the functionality of the expressed receptor. We also demonstrate unequivocally that oPL, through a specific interaction with the transfected oGH receptor, is able to mediate a similar cellular response (38% protein synthesis induction). Responsiveness to oGH and oPL in the GHR9.5 cells is dependent on serum starvation prior to oGH exposure and occurs only with prolonged exposure (greater than 2 h) to oGH. This cellular stimulation occurs independently of c-fos transcription which has previously been shown to be one of the earliest events associated with GH action in tissues expressing endogenous GH receptors (Doglio et al. (1989) Proc. Natl. Acad. Sci. USA 86, 1148-1152; Slootweg et al. (1990) J. Mol. Endocrinol. 4, 265-274).
Mol Cell Endocrinol 1992 Jul
PMID:Functional expression of an ovine growth hormone receptor in transfected Chinese hamster ovary cells. 151 79

3T3-L1 preadipocytes differentiate into cells having the biochemical properties of adipocytes; tumour necrosis factor-alpha (TNF) attenuates this process. Inhibition of differentiation by this cytokine, thought to be mediated at the level of transcription, has been investigated by examining the accumulation of mRNA for six transcription factors and three diversely regulated genes during the first 24 h of the differentiation process. Upon induction of differentiation, a rapid and major accumulation of c-fos and jun-B mRNA, which returned to near basal levels within 4-6 h, was observed. In contrast, c-jun mRNA, although rapidly expressed at the induction of differentiation, remained at relatively constant levels throughout the time-course. Exposure of the cells to 5 nM TNF potentiated the accumulation of all three mRNAs but most significantly that of c-jun (12-fold), which remained elevated for at least 24 h after treatment. In control differentiating cells, krox-20 and fos-B were expressed transiently from 30 min to 2 h, while fra-1 mRNA accumulated over an extended period of 1 to 8 h. Again, TNF enhanced the accumulation of these mRNAs. Accumulation of mRNA for C/EBP, a transcription factor proposed to control the expression of genes involved in the terminally differentiated state, was attenuated after exposure of the cells to TNF. Interleukin-6 (IL-6) mRNA was expressed briefly (30 min to 2 h) and again transiently (at 8 h after induction of differentiation). TNF treatment markedly enhanced accumulation of IL-6 message. We propose that an increased cellular content of one or more transcription factors or the suppression of C/EBP may be responsible for the attenuation of differentiation induced by exposure of the cells to TNF.
J Mol Endocrinol 1992 Aug
PMID:Regulation of transcription factor mRNA accumulation during 3T3-L1 preadipocyte differentiation by tumour necrosis factor-alpha. 151 26

The glutathione transferases, a family of multifunctional proteins, catalyze the glutathione conjugation reaction with electrophilic compounds biotransformed from xenobiotics, including carcinogens. In preneoplastic cells as well as neoplastic cells, specific molecular forms of glutathione transferase are known to be expressed and have been known to participate in the mechanisms of their resistance to drugs. In this article, following a brief description of recently identified molecular forms, we review new findings regarding the respective molecular forms involved in carcinogenesis and anticancer drug resistance, with particular emphasis on Pi class forms in preneoplastic tissues. The rat Pi class form, GST-P (GST 7-7), is strongly expressed not only in hepatic foci and hepatomas, but also in initiated cells that occur at the very early stages of chemical hepatocarcinogenesis, and is regarded as one of the most reliable markers for preneoplastic lesions in the rat liver. 12-O-Tetradecanoylphorbol-13-acetate (TPA)-responsive element-like sequences have been identified in upstream regions of the GST-P gene, and oncogene products c-jun and c-fos are suggested to activate the gene. The Pi-class forms possess unique enzymatic properties, including broad substrate specificity, glutathione peroxidase activity toward lipid hydroperoxides, low sensitivity to organic anion inhibitors, and high sensitivity to active oxygen species. The possible functions of Pi class glutathione transferases in neoplastic tissues and drug-resistant cells are discussed.
Crit Rev Biochem Mol Biol 1992
PMID:Glutathione transferases and cancer. 152 61


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