Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ubiquitin is a 76-amino acid protein whose sequence is highly conserved throughout evolution from invertebrates to mammals. It is both a cytoplasmic and nuclear protein. In the cytoplasm it is involved in ATP-dependent nonlysosomal proteolysis. In the nucleus, ubiquitin is conjugated to histone 2A and may play a role in regulation of chromatin structure and/or regulation of transcriptional activity. During attempts to identify a cDNA encoding somatomedin-C (insulin-like growth factor I) we screened a fetal human liver cDNA library with a mixture of 17 base oligonucleotides corresponding to a portion of the B chain of somatomedin-C. One oligonucleotide of the mixture hybridized to two cDNAs encoding ubiquitin despite a 2-base pair mismatch. Nucleotide sequence analyses of the 350- and 516-base pair cDNAs revealed that they correspond to the same ubiquitin mRNA. The coding sequence of the 516-base pair cDNA begins at amino acid 5 of the ubiquitin sequence and encodes amino acids 5 through 76 of ubiquitin, an 80-amino acid carboxy-terminal extension, a 3' untranslated region, and a poly(A) tail. The finding that ubiquitin is synthesized as a precursor raises the possibility that the precursor sequence may be important in compartmentalization of ubiquitin or ubiquitin precursors. Analyses of ubiquitin mRNAs in poly(A) RNA extracted from human liver and various rat tissues reveals that there are three distinct mRNAs encoding ubiquitin in humans and four mRNAs in the rat.
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PMID:Nucleotide sequence analysis of a cDNA encoding human ubiquitin reveals that ubiquitin is synthesized as a precursor. 258 67

Upon fasting, the ubiquitin-dependent proteolytic system is activated in skeletal muscle in parallel with the increases in rates of proteolysis. Levels of mRNA encoding the 14 kDa ubiquitin-conjugating enzyme (E2(14K)), which can catalyse the first irreversible reaction in this pathway, rise and fall in parallel with the rates of proteolysis [Wing and Banville (1994) Am.J. Physiol. 267, E39-E48], indicating that the conjugation of ubiquitin to proteins is a regulated step. To characterize the mechanisms of this regulation, we have examined the effects of insulin, insulin-like growth factor I (IGF-I) and des(1-3) insulin-like growth factor I (DES-IGF-I), which does not bind IGF-binding proteins, on E2(14K) mRNA levels in L6 myotubes. Insulin suppressed levels of E2(14K) mRNA with an IC50 of 4 x 10(-9) M, but had no effects on mRNAs encoding polyubiquitin and proteasome subunits C2 and C8, which, like E2(14K), also increase in skeletal muscle upon fasting. Reduction of E2(14K) mRNA levels was more sensitive to IGF-I with an IC50 of approx. 5 x 10(-10) M. During the incubation of these cells for 12 h there was significant secretion of IGF-I-binding proteins into the medium. DES-IGF-I, which has markedly reduced affinity for these binding proteins, was found to potently reduce E2(14K) mRNA levels with an IC50 of 3 x 10(-11) M. DES-IGF-I did not alter rates of transcription of the E2(14K) gene, but enhanced the rate of degradation of the 1.2 kb mRNA transcript. The half-life of the 1.2 kb transcript was approximately one-third that of the 1.8 kb transcript and can explain the more marked regulation of this transcript observed previously. This indicates that the additional 3' non-coding sequence in the 1.8 kb transcript confers stability. These observations suggest that IGF-I is an important regulator of E2(14K) expression and demonstrate, for the first time, stimulation of degradation of a specific mRNA transcript by this hormone, while overall RNA accumulates.
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PMID:Insulin-like growth factor I stimulates degradation of an mRNA transcript encoding the 14 kDa ubiquitin-conjugating enzyme. 891 81

We have sought to determine whether insulin-like growth factor I (IGF-I) regulates the levels of insulin receptor substrate-1 (IRS-1) in prostate epithelial cells. Exposure of prostate epithelial cells to IGF-I in the absence of other growth factors leads to a reduction in IRS-1 levels. Ubiquitin content of IRS-1 is increased in the presence of IGF-I, and inhibitors of the proteasome prevented the reduction of IRS-1 levels seen following IGF-I exposure. These results imply that IRS-1 is targeted to the proteasome upon exposure to IGF-I. The addition of epidermal growth factor (EGF) maintained IRS-1 levels even in the presence of IGF-I and inhibits IGF-I-dependent ubiquitination of IRS-1. Thus, these two growth factors, IGF-I and EGF, had antagonistic effects on IRS-1 protein levels in prostate epithelial cells. This regulation of IRS-1 reveals a novel level of cross-talk between the IGF-I and EGF signal pathways, which may have implications in tumors that harbor activating mutations in the EGF receptor.
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PMID:Insulin-like growth factor I-mediated degradation of insulin receptor substrate-1 is inhibited by epidermal growth factor in prostate epithelial cells. 1081 32

We examined the effect of insulin-like growth factor I (IGF-I), administered in vivo, on protein turnover rates and gene expression of the ubiquitin-proteasome proteolytic pathway in skeletal muscle of septic rats. Sepsis was induced by cecal ligation and puncture. Other rats were sham-operated. Miniosmotic pumps were implanted sc, and groups of rats received IGF-I (7 mg/kg x 24 h) or saline. Protein synthesis and breakdown rates were determined in incubated extensor digitorum longus muscles. Messenger RNA levels for ubiquitin and the ubiquitin-conjugating enzyme E2(14k) were determined by Northern blot analysis. Sepsis resulted in an approximately 30% reduction of muscle protein synthesis, and this effect of sepsis was blunted in rats treated with IGF-I. In contrast, IGF-I did not prevent the sepsis-induced increase in total and myofibrillar muscle protein breakdown. Ubiquitin and E2(14k) messenger RNA levels were increased several fold in muscle from septic rats, and this effect of sepsis was abolished in IGF-I treated rats. The results suggest that administration of IGF-I may improve sepsis-induced muscle cachexia by stimulating protein synthesis. However, because muscles were resistant to IGF-I, with regard to regulation of protein breakdown, the use of IGF-I to treat muscle cachexia during sepsis remains unclear. An additional important implication of the present study is that changes in messenger RNA levels for ubiquitin and the ubiquitin-conjugating enzyme E2(14k) do not always reflect changes in muscle protein breakdown rates.
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PMID:Insulin-like growth factor I reduces ubiquitin and ubiquitin-conjugating enzyme gene expression but does not inhibit muscle proteolysis in septic rats. 1091 58

Ubiquitination has been implicated in negatively regulating insulin-like growth factor I receptor (IGF-IR) activity. Because of the relative stability of IGF-IR in the presence of ligand stimulation, IGF-IR ubiquitination sites have yet to be mapped and characterized, thus preventing a direct demonstration of how the receptor ubiquitination contributes to downstream molecular cascades. We took advantage of an anti-IGF-IR antibody (h10H5) that induces more efficient receptor down-regulation to show that IGF-IR is promptly and robustly ubiquitinated. The ubiquitination sites were mapped to the two lysine residues in the IGF-IR activation loop (Lys-1138 and Lys-1141) and consisted of polyubiquitin chains formed through both Lys-48 and Lys-29 linkages. Mutation of these ubiquitinated lysine residues resulted in decreased h10H5-induced IGF-IR internalization and down-regulation as well as a reduced cellular response to h10H5 treatment. We have therefore demonstrated that IGF-IR ubiquitination contributes critically to the down-regulating and antiproliferative activity of h10H5. This finding is physiologically relevant because insulin-like growth factor I appears to mediate ubiquitination of the same major sites as h10H5 (albeit to a lesser extent), and ubiquitination is facilitated by pre-existing phosphorylation of the receptor in both cases. Furthermore, identification of a breast cancer cell line with a defect in IGF-IR ubiquitination suggests that this could be an important tumor resistance mechanism to evade down-regulation-mediated negative regulation of IGF-IR activity in cancer.
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PMID:Polyubiquitination of insulin-like growth factor I receptor (IGF-IR) activation loop promotes antibody-induced receptor internalization and down-regulation. 2199 39