Casein kinase 2 inhibition decreases hypoxia-inducible factor-1 activity under hypoxia through elevated p53 protein level.
J Cell Sci
; 119(Pt 16): 3351-62, 2006 Aug 15.
Article
em En
| MEDLINE
| ID: mdl-16882692
ABSTRACT
HIF-1 (hypoxia-inducible factor-1) is the main transcription factor involved in the adaptation of cells to hypoxia. In addition to regulation of HIF-1alpha protein level, HIF-1 activity is also enhanced by several pathways involving asparagine hydroxylation and phosphorylation. Here, we investigated the relationship between casein kinase 2 (CK2), p53 and HIF-1. An increase in p53 protein level and transcriptional activity was observed when CK2 was inhibited by different inhibitors under normoxia and hypoxia. This increase was in parallel with a decrease in HIF-1 activity without changes in HIF-1alpha protein level, indicating a regulation of its transcriptional activity. Similar results were obtained using CK2alpha siRNA. Ectopic overexpression of p53 also led to an inhibition of HIF-1 activity. Conversely, CK2 inhibition had no effect in p53-null cells indicating that the inhibitory effect of CK2 inhibitors requires the presence of p53. p53 activity was not required because overexpression of a p53 mutated in its DNA-binding domain exerted the same effect as wild-type p53 and because the effect of CK2 inhibitors was still observed when p53 activity was inhibited by pifithrin-alpha. Since CK2 activity is increased in hypoxic conditions, this process provides one more mechanism to ensure enhanced HIF-1 activity under such conditions.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína Supressora de Tumor p53
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Caseína Quinase II
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Subunidade alfa do Fator 1 Induzível por Hipóxia
Limite:
Humans
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article