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Casein kinase 1 regulates human hypoxia-inducible factor HIF-1
dc.creator | Kalousi, A. | en |
dc.creator | Mylonis, I. | en |
dc.creator | Politou, A. S. | en |
dc.creator | Chachami, G. | en |
dc.creator | Paraskeva, E. | en |
dc.creator | Simos, G. | en |
dc.date.accessioned | 2015-11-23T10:31:09Z | |
dc.date.available | 2015-11-23T10:31:09Z | |
dc.date.issued | 2010 | |
dc.identifier | 10.1242/jcs.068122 | |
dc.identifier.issn | 0021-9533 | |
dc.identifier.uri | http://hdl.handle.net/11615/28794 | |
dc.description.abstract | Hypoxia-inducible factor 1 (HIF-1), a transcriptional activator that mediates cellular response to hypoxia and a promising target of anticancer therapy, is essential for adaptation to low oxygen conditions, embryogenesis and tumor progression. HIF-1 is a heterodimer of HIF-1 alpha, expression of which is controlled by oxygen levels as well as by various oxygen-independent mechanisms, and HIF-1 beta (or ARNT), which is constitutively expressed. In this work, we investigate the phosphorylation of the N-terminal heterodimerization (PAS) domain of HIF-1 alpha and identify Ser247 as a major site of in vitro modification by casein kinase 1 delta (CK1 delta). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of HIF-1 alpha, a result phenocopied by inhibition or small interfering RNA (siRNA)-mediated silencing of CK1 delta under hypoxic conditions. Conversely, overexpression of CK1 delta or phosphomimetic mutation of Ser247 to aspartate inhibited HIF-1 alpha activity without affecting its stability or nuclear accumulation. Immunoprecipitation and in vitro binding experiments suggest that CK1-dependent phosphorylation of HIF-1 alpha at Ser247 impairs its association with ARNT, a notion also supported by modeling the structure of the complex between HIF-1 alpha and ARNT PAS-B domains. We suggest that modification of HIF-1 alpha by CK1 represents a novel mechanism that controls the activity of HIF-1 during hypoxia by regulating the interaction between its two subunits. | en |
dc.source | Journal of Cell Science | en |
dc.source.uri | <Go to ISI>://WOS:000281082500012 | |
dc.subject | HIF-1 | en |
dc.subject | Casein kinase | en |
dc.subject | CK1 | en |
dc.subject | PAS | en |
dc.subject | ARNT | en |
dc.subject | Hypoxia | en |
dc.subject | HYDROCARBON RECEPTOR COMPLEX | en |
dc.subject | ARNT TRANSCRIPTION FACTOR | en |
dc.subject | PAS-B DOMAIN | en |
dc.subject | IN-VIVO | en |
dc.subject | PHOSPHORYLATION SITES | en |
dc.subject | GENE-EXPRESSION | en |
dc.subject | DNA-BINDING | en |
dc.subject | C-MYC | en |
dc.subject | HIF-1-ALPHA | en |
dc.subject | FACTOR-1-ALPHA | en |
dc.subject | Cell Biology | en |
dc.title | Casein kinase 1 regulates human hypoxia-inducible factor HIF-1 | en |
dc.type | journalArticle | en |
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