Functions of the Per/ARNT/Sim domains of the hypoxia-inducible factor.
J Biol Chem
; 280(43): 36047-54, 2005 Oct 28.
Article
en En
| MEDLINE
| ID: mdl-16129688
ABSTRACT
The heterodimeric transcription factor hypoxia-inducible factor (HIF) plays an important role in the progression of a number of processes in which O2 availability is compromised and, as such, has become an increasingly attractive therapeutic target. Although tremendous progress has been made in recent years in unraveling the mechanisms underlying O2-dependent regulation of HIF through its O2-dependent degradation domain and C-terminal transactivation domain, our understanding of the contributions of other structural elements, particularly the Per/ARNT/Sim (PAS)-A and PAS-B domains, to the activity of HIF is incomplete. Using insights derived from the recently determined solution structures of the HIF PAS-B domains as a starting point, we have explored the function(s) of the HIF-2alpha PAS domains via mutational analysis. In contrast to recent models, our data reveal that both PAS domains of the HIF-alpha subunit are necessary for heterodimer formation but are not required to mediate other HIF functions in which PAS domains have been implicated. Because disruption of individual PAS domains compromise HIF function independent of the mechanism of HIF induction, these data demonstrate the potential utility of targeting these domains for therapeutic applications.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Factor 1 Inducible por Hipoxia
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Biol Chem
Año:
2005
Tipo del documento:
Article
País de afiliación:
Estados Unidos