Transcription Receptor-mediated HIF regulation
Receptor-mediated HIF regulation
Insulin and Insulin-like growth factor 1 ( IGF-1 ) induceHypoxia-inducible factor 1 alpha subunit ( HIF1A) [1], [2] and HIF-induced Vascular endothelial growth factor ( VEGF ) expression[3], [1], [2] and Insulin-like growth factorbinding protein 3 ( IBP3 ) [4].
IGF-1 induces HIF1A protein synthesis via Mitogen-activated proteinkinase 1 and 3 ( Erk (MAPK1/3) ) and Phosphoinositide-3-kinase ( PI3K)-dependent pathway that can involve Eukaryotic translation initiation factor 4E (eIF4E ), Ribosomal protein S6 kinase 70kDa polypeptide (for example p70 S6kinase2 ) [5] and 3-phosphoinositide dependent protein kinase-1 ( PDK(PDPK1) )-dependent activation of FK506 binding protein 12-rapamycin associatedprotein 1 ( mTOR ) [1]. IGF-1 binds IGF-1 receptorwhich possesses tyrosine kinase activity. IGF-1 receptor phosphorylates Insulinreceptor substrate ( IRS ) and then IGF-1 receptor causes the sequentialphosphorylation of PI3K, PDK, V-akt murine thymoma viral oncogene homolog1 ( AKT(PKB) ), and mTOR. PI3K and PDK activation mediateIGF-1 -induced activation of p70 S6 kinase2 [6], [7]. Recruitment to both IRS-1 and SHC transforming protein 1 ( Shc )via the SH2 domain of the adaptor Growth factor receptor-bound protein 2 ( Grb2 )leads to possible activation of V-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras ) that in turn activates the protein serine kinase, possibly the V-raf-1murine leukemia viral oncogene homolog 1 ( c-Raf-1 ), and ERK cascade[7]. And then, via MAP kinase interacting serine/threonine kinase (MNK ) and eIF4E, IGF-1 receptor induces HIF1A proteinsynthesis [5].
Insulin stimulates HIF1A through PI3K/ mTOR -dependentsignaling pathway [8], [1]. The binding of Insulin tothe extracellular domain of the Insulin receptor results in the activationof the tyrosine kinase activity of the receptor. Insulin receptor via IRSactivates the same PI3K -pathway as described above [9].
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