Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deletion of the type 1 insulin-like growth factor receptor (IGF-IR) or of the insulin receptor substrate-1 (IRS-1) genes in animals causes a 50% reduction in body size at birth. Decrease in body size is due to both a decreased number of cells and a decreased cell size. Deletion of the insulin receptor (InR) genes results in mice that are normal in size at birth. We have used 32D-derived myeloid cells to study the effect of IGF-IR and InR signaling on cell size. 32D cells expressing the IGF-IR and IRS-1 are almost twice as large as 32D cells expressing the InR and IRS-1. A mechanism for the difference in size is provided by the levels of the upstream binding factor 1 (UBF1), a nucleolar protein that participates in the regulation of RNA polymerase I activity and rRNA synthesis and therefore cell size. When shifted to the respective ligands, UBF1 levels decrease in cells expressing the InR and IRS-1, whereas they remain stable in cells expressing the IGF-IR and IRS-1. The expression of the IGF-IR and IRS-1 is crucial to the stability of UBF1.
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PMID:A mechanism for cell size regulation by the insulin and insulin-like growth factor-I receptors. 1714 51

Cell size plays an indirect role in cell proliferation, as cells must double in size before dividing. Cell size is largely determined by the activity of RNA polymerase I that controls ribosomal RNA synthesis and ribosome biogenesis. The type 1 insulin-like growth factor receptor (IGF-IR) and its docking protein, insulin receptor substrate-1 (IRS-1) control, in a non-redundant way, about 50% of cell and body size. This is certainly true in mice, flies and cells in culture, but also probably in higher mammals. Interestingly, the insulin receptor (InR) cannot substitute for the IGF-IR in controlling cell size. This is probably due to the fact that the IGF-IR is more effective than the InR in translocationg to the nuclei IRS-1, which then binds UBF1, one of the proteins that regulate RNA pol I activity.
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PMID:Is cell size important? 1740 3

The Upstream Binding Factor 1 (UBF1) is a nucleolar protein that participates in the regulation of RNA polymerase I activity and ribosomal RNA (rRNA) synthesis. In 32D myeloid cells expressing the type 1 insulin-like growth factor receptor (IGF-IR), the UBF1 protein (but not its mRNA) is down regulated when the cells are shifted from Interleukin-3 (IL-3) to IGF-1. Ectopic expression of insulin receptor substrate-1 (IRS-1) in these cells inhibits the down-regulation of UBF1. We now show that the stability of UBF1 in 32D-derived cells requires also a signal from the extracellular regulated kinases (ERKs). When ERKs signaling is defective, as in cells over-expressing the insulin receptor (InR) or selected mutants of the IGF-1R, UBF1 is down-regulated, even in the presence of IRS-1. The down-regulation is corrected by the expression of an activated Ha-ras, which stimulates ERKs activity. Mutations at threonines 117 and 201 of UBF1, known to be phosphorylated by ERKs, cause its down-regulation. However, when IRS-2, instead of IRS-1, is ectopically expressed in 32D InR cells, ERKs phosphorylation is increased and UBF is stabilized. Taken together, these results indicate that in 32D-derived myeloid cells expressing either the IGF-IR or the InR, UBF1 levels are regulated by signaling from both IRS proteins and ERKs.
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PMID:Dual regulation of upstream binding factor 1 levels by IRS-1 and ERKs in IGF-1-receptor signaling. 1744 74

Although much is known about the molecular players in insulin signaling, there is scant information about transcriptional regulation of its key components. We now find that NUCKS is a transcriptional regulator of the insulin signaling components, including the insulin receptor (IR). Knockdown of NUCKS leads to impaired insulin signaling in endocrine cells. NUCKS knockout mice exhibit decreased insulin signaling and increased body weight/fat mass along with impaired glucose tolerance and reduced insulin sensitivity, all of which are further exacerbated by a high-fat diet (HFD). Genome-wide ChIP-seq identifies metabolism and insulin signaling as NUCKS targets. Importantly, NUCKS is downregulated in individuals with a high body mass index and in HFD-fed mice, and conversely, its levels increase upon starvation. Altogether, NUCKS is a physiological regulator of energy homeostasis and glucose metabolism that works by regulating chromatin accessibility and RNA polymerase II recruitment to the promoters of IR and other insulin pathway modulators.
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PMID:NUCKS is a positive transcriptional regulator of insulin signaling. 2493 9


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