Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.27.1 (RNase)
16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue distribution and potential alternative splicing of insulin-like growth factor I (IGF-I) messenger RNA were studied using reverse transcriptase-polymerase chain reaction (RT-PCR) on RNA from several tissues at various stages of the life cycle of coho salmon (Oncorhynchus kisutch). DNA sequence analysis of RT-PCR products revealed three IGF-I mRNA transcripts, designated Ea-1, Ea-2, and Ea-3, which code for three distinct prohormones, IGF-IA-1, IGF-IA-2, and IGF-IA-3, respectively. The E-domain of proIGF-IA-1 is 35 amino acids long and shares 77% sequence identity with the E-domain of human proIGF-IA, which is also 35 amino acids long. The proIGF-IA-2 and proIGF-IA-3 E-domains are homologous to the proIGF-IA-1 E-domain but contain 27 and 39 amino acid inserts, respectively, between Lys86 and Glu87. In the human IGF-I gene Lys86 is coded by exon 4 and Glu87 is coded by exon 6. This suggests that Ea-2 and Ea-3 transcripts may be the result of alternative splicing during pre-mRNA processing. All three transcripts were readily detectable using a solution hybridization/RNase protection assay. Furthermore, RT-PCR and DNA sequencing analysis indicate the presence of three IGF-I prohormones in another member of the Salmonidae family, the Atlantic salmon (Salmo salar). An analysis of IGF-I and -II E-domains from several vertebrates suggests that certain chemical and physical properties of the molecule are well conserved despite wide variations in primary structure. Ea-1, Ea-2, and Ea-3 transcripts were found in whole embryos, and liver, muscle, and brain of juvenile and adult salmon. At least one IGF-I transcript was found in heart, kidney, testes, ovary, adipose tissue, and spleen of juvenile salmon. These results indicate that IGF-I is expressed during embryonic development of fish, and that most tissues are capable of IGF-I mRNA production. These data also indicate that pre-mRNA transcripts can be alternatively spliced to yield at least three prohormones.
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PMID:Nucleotide sequence and tissue distribution of three insulin-like growth factor I prohormones in salmon. 140 98

Many of the growth-promoting properties of GH are mediated by insulin-like growth factor I (IGF-I), a highly conserved circulating 70-amino acid peptide. Recent studies have shown that multiple mechanisms influence IGF-I gene expression, including transcription from two promoters, alternative RNA splicing, and variable polyadenylation. In order to determine how GH regulates IGF-I gene expression we have analyzed the response of hypophysectomized rats to a single ip injection of recombinant GH. A rise in hepatic IGF-I mRNA was detected within 2 h of GH treatment, with peak values of more than 15-fold above untreated animals by 4 h, and a decline by 16 h. A coordinate increase was seen in all IGF-I mRNA splicing and polyadenylation variants, indicating that neither alternative RNA processing nor differential poly A addition were altered by GH. Transcription run-on experiments using isolated hepatic nuclei and direct analysis of nuclear RNA demonstrated a rise in nascent IGF-I mRNA within 30 min of GH treatment, with peak levels reaching more than 10-fold above background by 2 h and declining by 6 h. As determined by RNase protection assays, transcripts directed by each promoter were coordinately and equivalently activated after GH. A single GH-responsive DNase I hypersensitive site was mapped in chromatin to the second IGF-I intron. This site exhibited rapid kinetics of induction which mirrored the pattern of transcriptional stimulation after GH treatment. These experiments show that GH enhances IGF-I expression in vivo by predominantly transcriptional mechanisms. The rapid kinetics of IGF-I gene activation and the temporally associated chromatin changes demonstrate a direct link between a GH-dependent signal transduction pathway and nuclear events.
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PMID:Growth hormone rapidly activates insulin-like growth factor I gene transcription in vivo. 148 Jan 77

In rat liver, insulin-like growth factor I (IGF-I) mRNAs exist as two major size classes of 7.5-7.0 kb and 1.2-0.9 kb. The 7.5- to 7.0-kb IGF-I mRNAs predominate in some nonhepatic tissues of the rat. Because the previously reported sequences of rat IGF-I cDNAs and genomic clones account for only 2.1 kb of sequence, the majority of the sequence of 7.5- to 7.0-kb rat IGF-I mRNAs was unknown. Using a combination of nucleotide sequencing of genomic DNA and cDNA clones and Northern hybridization and RNase protection, we have characterized a 6,354-base-long 3' exon (exon 6) of the rat IGF-I gene. The sequence of exon 6 establishes the previously unknown sequence of the 3' end of the 7.5- to 7.0-kb rat IGF-I mRNAs, comprised predominantly of an unusually long 3' untranslated sequence (3'UT). The long 3'UT contains multiple ATTTA, A(T)nA, and (T)nA sequences, as well as inverted repeats. These sequences may contribute to the shorter half-life of the 7.5- to 7.0-kb rat IGF-I mRNAs relative to the 1.2- to 0.9-kb forms that have been demonstrated previously in vitro and in vivo. We also demonstrate that the 7.5- to 7.0-kb rat IGF-I mRNAs are localized to the cytoplasm of rat liver, providing indirect evidence that they are mature and functional mRNAs.
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PMID:Structural characterization of exon 6 of the rat IGF-I gene. 152 77

The growth of rat glioma C6 cells, which provide an in vitro model of glial cells, is inhibited by retinoic acid and glucocorticoids, two agents which are important in brain differentiation and growth. To determine whether the growth-inhibitory effects of these agents are mediated by alterations in insulin-like growth factor I (IGF-I) production, the effects of retinoic acid and dexamethasone on IGF-I production and messenger RNA levels in C6 cells were investigated. IGF-I mRNA levels were determined using a solution hybridization/RNase protection assay. Treatment of C6 cells with dexamethasone or retinoic acid decreased IGF-I mRNA levels in a time-dependent fashion. The time course of the effect of the two agents differed, with the peak effect of dexamethasone between 6 and 12 h and the peak effect of retinoic acid at 27 h. In dose-response studies, IGF-I mRNA levels decreased to 27% of control levels (cells maintained in serum-free media) after treatment with 5 ng/ml dexamethasone, while half-maximal inhibition was achieved with approximately 0.5 ng/ml (1.4 nM) dexamethasone. Treatment with 10 microM retinoic acid decreased IGF-I mRNA levels to 24% of control levels with half-maximal inhibition occurring with approximately 0.5 microM retinoic acid. Cycloheximide prevented the inhibitory effect of these agents on IGF-I mRNA levels, suggesting that their effect is at least partly dependent upon protein synthesis. Immunoreactive IGF-I levels in media conditioned for 48 h by cells treated with dexamethasone or retinoic acid decreased to 32% and 42% of control levels, respectively. Treatment of C6 cells with retinoic acid or dexamethasone decreased thymidine incorporation into DNA. Treatment of cells with IGF-I alone had no effect on thymidine incorporation into DNA, but addition of 10 or 50 ng/ml IGF-I to dexamethasone-treated cells stimulated a small, but significant (P less than 0.01), increase in thymidine incorporation into DNA. IGF-I was not, however, able to reverse the inhibitory effect of retinoic acid. Finally, treatment of cells with 150 ng/ml of IGF binding protein 1 significantly decreased (P less than 0.01) thymidine incorporation into DNA by 17% as compared to incorporation into control cells maintained in serum-free media.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of insulin-like growth factor I production in rat C6 glioma cells: possible role as an autocrine/paracrine growth factor. 157 88

The expression of mRNAs encoding insulin-like growth factor I (IGF-I) and the IGF-I receptor in the developing rat brain from embryonic day 16 to postnatal day 82 was analyzed using solution hybridization-RNase protection assays. Four distinct developmental patterns in the steady-state levels of IGF-I mRNA were seen. Specifically, the olfactory bulb showed a high perinatal level of IGF-I mRNA which declined dramatically by postnatal day 8. In contrast, cerebral cortex displayed maximal levels of IGF-I mRNA at postnatal day 8 and 13, which subsequently declined to adult levels (P82). A third developmental pattern was seen in the hypothalamus, where IGF-I mRNA increased from E16 up to postnatal day 3 and remained elevated thereafter. Finally, IGF-I mRNA levels in brainstem and cerebellum remained unchanged throughout the time period studied. We conclude that there are specific regional patterns of IGF-I gene expression in the developing rat brain. In contrast, IGF-I receptor gene expression did not exhibit any region-specific developmental changes. The developmental patterns of IGF-I gene expression seen in this study further substantiate the potential role of IGF-I in normal brain development.
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PMID:Insulin-like growth factor I mRNA levels are developmentally regulated in specific regions of the rat brain. 164 81

Oligodendrocyte progenitor cells were prepared by mechanical dissociation of 1-day-old rat brain cultures. These cells undergo proliferation and differentiation into oligodendrocytes as demonstrated by the expression of proliferation and differentiation-related specific antigens. We have used this unique culture system to characterize insulin-like growth factor I (IGF-I) receptors and their action in the central nervous system (CNS). 125I-IGF-I specifically binds to these cultures with high affinity. Competition-inhibition data suggest that IGF-I is most potent in competing for 125I-IGF-I binding, followed by IGF-II and insulin. Scatchard analyses of the binding data indicate a curvilinear plot with a Kd for high affinity of 0.2 nM, and a Bmax of 247 fmol/mg, and a Kd for low affinity of 3.2 nM and Bmax of 1213 fmol/mg protein. Covalent cross-linking followed by SDS-PAGE analysis demonstrated a radioactive band of Mr 135,000 which corresponds to the alpha subunit of the IGF-I receptor. Solution hybridization/RNase protection assay produced a single protected band corresponding to IGF-I receptor messenger RNA, further confirming the presence of these receptors. Incubation of progenitor cells with IGF-I resulted in a time- and concentration-dependent increase in [3H]thymidine incorporation and cell numbers. This effect appears to be mediated by IGF-I receptors since IGF-II and insulin were proportionately less potent. In addition to its effect on proliferation, IGF-I also increased the number of 4E7- and GC-antigen positive cells. These observations indicate that oligodendrocytes in primary culture express specific IGF-I receptors and that the interaction of IGF-I with these receptors results in the proliferation as well as differentiation of oligodendrocytes.
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PMID:Insulin-like growth factor I (IGF-I) receptors and IGF-I action in oligodendrocytes from rat brains. 165 76

Fibroblasts represent one of the in vivo sites of extrahepatic insulin-like growth factor I (IGF-I) production. In this study, cultured fibroblasts prepared from the skin of neonatal rats were used as a model to assess the role of serum in regulating IGF-I messenger RNA (mRNA) levels. IGF-I mRNA, as demonstrated by Northern blot analysis, was present in the cultured fibroblasts, and serum free media which was conditioned by fibroblasts for 20 h contained 108 pg/ml of immunoreactive IGF-I. Fetal calf serum (FCS) decreased steady state IGF-I mRNA levels, as measured by solution hybridization/RNase protection assay, in fibroblasts in a time- and dose-dependent fashion. Incubation of fibroblasts for 18 h in the presence of 0.3%, 0.6%, or 1% FCS decreased IGF-I mRNA levels to 76%, 56%, and 46% of the levels present in control cells which were maintained in serum free media with 0.25% BSA. Maximal inhibition to approximately 20% of control levels was seen with 4-10% FCS. In contrast, basic fibroblast growth factor and beta-actin mRNA levels increased 2- and 4-fold, respectively, with increasing concentrations of FCS. Treatment of the cells with 10 micrograms/ml cycloheximide resulted in partial abrogation of the inhibitory effect of FCS while protein synthesis in the cells was decreased to 6% of control levels. The addition of 2 micrograms/ml of insulin or 15-100 ng/ml of IGF-I to the fibroblasts did not reproduce the inhibitory effect of FCS. Finally, the inhibitory factor(s) present in the FCS was partially removed/inactivated by charcoal stripping or heat inactivating the serum, but delipidation of the FCS by chloroform extraction had no effect on the inhibitory effect of FCS. In summary, FCS contains a factor(s) that decreases IGF-I mRNA levels in cultured fibroblasts in a time- and dose-dependent fashion. The partial abrogation of the inhibitory effect of FCS with cycloheximide treatment suggests that this effect is at least partially dependent upon new protein synthesis. Furthermore, the studies using delipidated, heat-inactivated, and charcoal-stripped serum suggest that the inhibitory factor(s) is a peptide.
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PMID:Regulation of insulin-like growth factor I messenger ribonucleic acid levels by serum in cultured rat fibroblasts. 170 Nov 30

Expression of the rat insulin-like growth factor I (IGF-I) gene results in a number of mature mRNA species that differ in size primarily at the 3' end due to differential polyadenylation site usage. Additionally, alternate splicing in both 5' and 3' regions produces RNAs which have the capacity to encode different IGF-I precursor peptides. We have analyzed total and polysomal RNAs using Northern blot analyses and solution hybridization/RNase protection assays to assess the in vivo translatability of these various IGF-I mRNA species. The results suggest that all of the known splicing variants are found on polysomes and may, therefore, be translated into a number of IGF-I precursors in vivo. One particular 5'-untranslated (UTR) variant is relatively enriched in polysomal RNA, a finding which suggests that removal of some of the 5'-UTR sequences encoded by exon 1 may enhance translatability. Of the IGF-I mRNAs with different lengths of 3'-UTR, only the shorter species were found on polysomes, suggesting that some aspect of the long 3'-UTR may prevent translation. Thus, differential processing of the primary transcript of the IGF-I gene may serve to generate IGF-I mRNA species which specify different precursors as well as to control their relative translatability.
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PMID:Differential association of insulin-like growth factor I mRNA variants with polysomes in vivo. 201 30

We have investigated the developmental regulation of the rat insulin-like growth factor I (IGF-I) receptor gene in various tissues using a sensitive and specific solution hybridization/RNase protection assay. For this purpose we characterized rat IGF-I receptor cDNAs that were cloned from a simian virus 40-transformed rat granulosa cell cDNA library. The specific cDNA clone used in these studies encoded the putative signal peptide and the first 53 amino acids of the alpha subunit and was approximately 94% homologous to its human counterpart. IGF-I receptor gene expression was studied during the perinatal period and at various intervals until early adulthood. Overall, steady-state IGF-I receptor mRNA levels decreased dramatically during postnatal development; however, the extent of the decrease differed among the various tissues studied. In contrast to receptor mRNA levels, IGF-I mRNA levels increased in some of the same tissues. The molecular mechanisms underlying this apparent divergent transcriptional control of the IGF-I and IGF-I receptor genes warrant further study.
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PMID:Developmental regulation of the rat insulin-like growth factor I receptor gene. 247 43

Solution hybridization/RNase protection assays were used to study the developmental expression of insulin-like growth factor I (IGF-I) mRNA levels in rats. In liver, heart, and kidney, total IGF-I mRNA levels were low at birth and increased during the 50-day postnatal period, with liver levels increasing by over 100-fold. In contrast, stomach, muscle, and testicular IGF-I mRNA levels were highest at the earliest stages examined (late fetal or early neonatal) and declined thereafter to the levels observed in 50-day-old rats. In brain, IGF-I mRNA levels rose 2-fold during the first week of life and declined over the next 6-7 weeks. Lung IGF-I mRNA levels were highest in 20-day-old fetuses and exhibited some fluctuation during the postnatal period. Alternative splicing in the 5'-untranslated region of the primary rat IGF-I transcript gives rise to three transcripts, classes A, B, and C, which have divergent 5'-untranslated region sequences associated with a common region that encodes the mature IGF-I peptide. These sequences contain upstream in-frame translation initiation codons and may, therefore, encode alternate IGF-I prepropeptides. The class C variant was the predominant mRNA species at all stages of development studied and was the only IGF-I transcript in brain, heart, and muscle. In tissues where multiple 5'-untranslated region splicing variants occurred, therefore, changes in total IGF-I mRNA primarily reflected changes in this splicing variant. However, the class C and class A (as well as class B in liver) transcripts exhibited temporally divergent changes over some developmental intervals. Class A transcripts in the liver, stomach, testes, and lung as well as class B transcripts in liver, exhibited sustained increases from 15 or 22 postnatal days to maximal levels at 50 postnatal days. In kidney, class A transcripts also increased steadily, but beginning at an earlier stage, i.e. at 8-15 days of postnatal life. These results demonstrate that the temporal expression of total IGF-I mRNA in the developing rat occurs in a tissue-specific manner, and additionally, that IGF-I mRNA variants are differentially expressed during development.
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PMID:Insulin-like growth factor I messenger ribonucleic acids with alternative 5'-untranslated regions are differentially expressed during development of the rat. 272 44


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