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Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch
David Lando,1Daniel J. Peet,1Dean A. Whelan,2Jeffrey J. Gorman,2Murray L. Whitelaw1*
The hypoxia-inducible factors (HIFs) 1 and 2 are key
mammalian transcription factors that exhibit dramatic increases inboth
protein stability and intrinsic transcriptional potency duringlow-oxygen stress. This increased stability is due to the absenceof
proline hydroxylation, which in normoxia promotes binding ofHIF to the
von Hippel-Lindau (VHL tumor suppressor) ubiquitinligase. We
now show that hypoxic induction of the COOH-terminaltransactivation
domain (CAD) of HIF occurs through abrogationof hydroxylation of a
conserved asparagine in the CAD. Inhibitorsof Fe(II)- and
2-oxoglutarate-dependent dioxygenases preventedhydroxylation of the
Asn, thus allowing the CAD to interact withthe p300 transcription
coactivator. Replacement of the conservedAsn by Ala resulted in
constitutive p300 interaction and strongtranscriptional activity. Full
induction of HIF-1 and -2, therefore,relies on the abrogation of
both Pro and Asn hydroxylation, whichduring normoxia occur at the
degradation and COOH-terminal transactivationdomains, respectively.
1 Department of Molecular Biosciences
(Biochemistry), Adelaide University, SA 5005, Australia.
2 CSIRO Health Sciences and Nutrition, 343 Royal
Parade, Parkville, VIC 3052, Australia.
*
To whom correspondence should be addressed. E-mail:
murray.whitelaw{at}adelaide.edu.au
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Cell-specific Regulation of Hypoxia-inducible Factor (HIF)-1{alpha} and HIF-2{alpha} Stabilization and Transactivation in a Graded Oxygen Environment.
C. P. Bracken, A. O. Fedele, S. Linke, W. Balrak, K. Lisy, M. L. Whitelaw, and D. J. Peet (2006)
J. Biol. Chem.
281, 22575-22585
|Abstract »|Full Text »|PDF »
Proteasomal Inhibition Attenuates Transcriptional Activity of Hypoxia-Inducible Factor 1 (HIF-1) via Specific Effect on the HIF-1{alpha} C-Terminal Activation Domain.
S. Kaluz, M. Kaluzova, and E. J. Stanbridge (2006)
Mol. Cell. Biol.
26, 5895-5907
|Abstract »|Full Text »|PDF »
Hypoxia and Expression of Hypoxia-Inducible Factor in the Aging Kidney.
T. Tanaka, H. Kato, I. Kojima, T. Ohse, D. Son, T. Tawakami, T. Yatagawa, R. Inagi, T. Fujita, and M. Nangaku (2006)
J Gerontol A Biol Sci Med Sci
61, 795-805
|Abstract »|Full Text »|PDF »
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