Casein kinase 1 regulates human hypoxia-inducible factor HIF-1 (Journal article)

Kalousi, A./ Mylonis, I./ Politou, A. S./ Chachami, G./ Paraskeva, E./ Simos, G.

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-1alpha, expression of which is controlled by oxygen levels as well as by various oxygen-independent mechanisms, and HIF-1beta (or ARNT), which is constitutively expressed. In this work, we investigate the phosphorylation of the N-terminal heterodimerization (PAS) domain of HIF-1alpha and identify Ser247 as a major site of in vitro modification by casein kinase 1delta (CK1delta). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of HIF-1alpha, a result phenocopied by inhibition or small interfering RNA (siRNA)-mediated silencing of CK1delta under hypoxic conditions. Conversely, overexpression of CK1delta or phosphomimetic mutation of Ser247 to aspartate inhibited HIF-1alpha activity without affecting its stability or nuclear accumulation. Immunoprecipitation and in vitro binding experiments suggest that CK1-dependent phosphorylation of HIF-1alpha at Ser247 impairs its association with ARNT, a notion also supported by modeling the structure of the complex between HIF-1alpha and ARNT PAS-B domains. We suggest that modification of HIF-1alpha by CK1 represents a novel mechanism that controls the activity of HIF-1 during hypoxia by regulating the interaction between its two subunits.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
Keywords: Amino Acid Sequence,Casein Kinase Idelta/genetics/*metabolism,Cell Hypoxia/physiology,HEK293 Cells,HeLa Cells,Humans,Hypoxia-Inducible Factor 1/genetics/*metabolism,Hypoxia-Inducible Factor 1, alpha Subunit/metabolism,Models, Molecular,Molecular Sequence Data,Nuclear Proteins/genetics/metabolism,Phosphorylation,Transcription Factors/genetics/metabolism,Transcriptional Activation
ISSN: 1477-9137
Appears in Collections:Άρθρα σε επιστημονικά περιοδικά ( Ανοικτά)

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