Abstract
The heterodimeric transcription factor hypoxia-inducible factor (HIF) plays an important role in the progression of a number of processes in which O 2 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 O 2-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-2α PAS domains via mutational analysis. In contrast to recent models, our data reveal that both PAS domains of the HIF-α 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 36047-36054 |
| Number of pages | 8 |
| Journal | Journal of Biological Chemistry |
| Volume | 280 |
| Issue number | 43 |
| DOIs | |
| State | Published - Oct 28 2005 |
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ASJC Scopus subject areas
- Biochemistry
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Functions of the Per/ARNT/Sim domains of the hypoxia-inducible factor. / Yang, Jinsong; Zhang, Lei; Erbel, Paul J A; Gardner, Kevin H.; Ding, Kan; Garcia, Joseph A.; Bruick, Richard K.
In: Journal of Biological Chemistry, Vol. 280, No. 43, 28.10.2005, p. 36047-36054.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Functions of the Per/ARNT/Sim domains of the hypoxia-inducible factor
AU - Yang, Jinsong
AU - Zhang, Lei
AU - Erbel, Paul J A
AU - Gardner, Kevin H.
AU - Ding, Kan
AU - Garcia, Joseph A.
AU - Bruick, Richard K.
PY - 2005/10/28
Y1 - 2005/10/28
N2 - The heterodimeric transcription factor hypoxia-inducible factor (HIF) plays an important role in the progression of a number of processes in which O 2 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 O 2-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-2α PAS domains via mutational analysis. In contrast to recent models, our data reveal that both PAS domains of the HIF-α 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.
AB - The heterodimeric transcription factor hypoxia-inducible factor (HIF) plays an important role in the progression of a number of processes in which O 2 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 O 2-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-2α PAS domains via mutational analysis. In contrast to recent models, our data reveal that both PAS domains of the HIF-α 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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U2 - 10.1074/jbc.M501755200
DO - 10.1074/jbc.M501755200
M3 - Article
C2 - 16129688
AN - SCOPUS:26244432309
VL - 280
SP - 36047
EP - 36054
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 43
ER -