What question did this study set out to answer?

To determine the molecular mechanism regulating the transcriptional potency of the hypoxia-inducible factor (HIF) COOH-terminal transactivation domain during hypoxic stress.

February 1, 2002Science

Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch

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Authors

DLDavid LandoUniversity of Cambridge DPDaniel J. PeetThe University of Adelaide DWDean A. WhelanCommonwealth Scientific and Industrial Research Organisation

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Implication

Biochemical study demonstrates that blocking asparagine hydroxylation triggers HIF transactivation domain binding to p300 in mammalian cells, indicating dual hydroxylations control oxygen sensing.

Key Points

To determine the molecular mechanism regulating the transcriptional potency of the hypoxia-inducible factor (HIF) COOH-terminal transactivation domain during hypoxic stress.
Evaluated the effect of Fe(II)- and 2-oxoglutarate-dependent dioxygenase inhibitors on HIF COOH-terminal transactivation domain (CAD) asparagine hydroxylation and p300 coactivator recruitment.
Engineered site-directed alanine mutations at the conserved CAD asparagine residue (Asn to Ala) to analyze transcriptional activity and p300 interaction independently of oxygen levels.
Hypoxia or small-molecule dioxygenase inhibitors suppressed hydroxylation of a conserved asparagine residue within the CAD, enabling the domain to bind the p300 transcription coactivator.
Substitution of the conserved asparagine with alanine produced constitutive interaction with p300 and strong transcriptional activation in the absence of hypoxic signaling.
Complete functional activation of HIF-1alpha and HIF-2alpha requires the abrogation of both proline hydroxylation at the degradation domain and asparagine hydroxylation at the transactivation domain.

Cite This Study

Lando et al. (2002) studied this question.

synapsesocial.com/papers/69d7bb2105ee2ba81dbed8dc https://doi.org/10.1126/science.1068592

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Implication

Biochemical study demonstrates that blocking asparagine hydroxylation triggers HIF transactivation domain binding to p300 in mammalian cells, indicating dual hydroxylations control oxygen sensing.

Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch

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Implication

Key Points

Cite This Study

Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch

Discussion

Member takes

Implication

Key Points

Cite This Study

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