Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of IGF-binding protein-1 (IGFBP-1) is induced in rat liver by dexamethasone and glucagon and is completely inhibited by 100 nM insulin. Various studies have implicated phosphatidylinositol 3-kinase, protein kinase B (Akt), phosphorylation of the transcription factors forkhead in rhabdomyosarcoma 1 (Foxo1)/Foxo3, and the mammalian target of rapamycin (mTOR) in insulin's effect. In this study we examined insulin regulation of IGFBP-1 in both subconfluent and confluent hepatocytes. In subconfluent hepatocytes, insulin inhibition of IGFBP-1 mRNA levels was blocked by inhibiting PI3 kinase activation, and there was a corresponding inhibition of Foxo1/Foxo3 phosphorylation. In these same cells, inhibition of the insulin effect by rapamycin occurred in the presence of insulin-induced Foxo1/Foxo3 phosphorylation. In confluent hepatocytes, insulin could not activate the phosphatidylinositol 3-kinase (PI3 kinase)-Akt-Foxo1/Foxo3 pathway, but still inhibited IGFBP-1 gene expression in an mTOR-dependent manner. In subconfluent hepatocytes, the serine/threonine phosphatase inhibitor okadaic acid (100 nM) partially inhibited IGFBP-1 gene expression by 40%, but did not produce phosphorylation of either Akt or Foxo proteins. In contrast, 1 nm insulin inhibited the IGFBP-1 mRNA level by 40% and correspondingly activated Akt and Foxo1/Foxo3 phosphorylation to a level comparable to that observed with 100 nM insulin. These results suggest a potential role for a serine/threonine phosphatase(s) in the regulation of IGFBP-1 gene transcription, which is not downstream of mTOR and is independent of Akt. In conclusion, we have found that in rat liver, insulin inhibition of IGFBP-1 mRNA levels can occur in the absence of the phosphorylation of Foxo1/Foxo3, whereas activation of the mTOR pathway is both necessary and sufficient.
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PMID:Regulation of hepatic insulin-like growth factor-binding protein-1 gene expression by insulin: central role for mammalian target of rapamycin independent of forkhead box O proteins. 1645 81

A 69-year-old woman was diagnosed with alveolar rhabdomyosarcoma (ARMS) of the nasopharynx. She has a history of catastrophic thromboembolic event in the abdomen that caused short-gut syndrome and dependence on total parenteral nutrition (TPN) twelve hours per day. She was treated for short-gut syndrome with teduglutide, a glucagon-like peptide-2 (GLP-2) analog, which led to reduction of TPN requirements. However, a few months later, she developed metastatic alveolar rhabdomyosarcoma. Though a causative relationship is unlikely between the peptide and ARMS due to the brief time course between teduglutide therapy and sarcoma diagnosis, neoplastic growth may have been accelerated by the GLP-2 analog, causing release of IGF-1. The transmembrane receptor for IGF-1 is frequently overexpressed in ARMS and is implicated in cell proliferation and metastatic behavior. This case describes a rare incidence of metastatic alveolar rhabdomyosarcoma in a sexagenarian and possibly the first case reported associated with the use of teduglutide. Teduglutide was discontinued due to a potential theoretical risk of acceleration of sarcoma growth, and the patient's rhabdomyosarcoma is in remission following sarcoma chemotherapy.
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PMID:Alveolar Rhabdomyosarcoma in a 69-Year-Old Woman Receiving Glucagon-Like Peptide-2 Therapy. 2626 67