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Regulation of the hypoxia-inducible factor-1 alpha. ARNT is not necessary for hypoxic induction of HIF-1 alpha in the nucleus.


Gassmann, M; Chilov, D; Wenger, R H (2000). Regulation of the hypoxia-inducible factor-1 alpha. ARNT is not necessary for hypoxic induction of HIF-1 alpha in the nucleus. In: Lahiri, S; Prabhaker, N; Forster, R. Oxygen Sensing: Molecule to Man. New York: Kluwer, 87-99.

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a master regulator of mammalian oxygen homeostasis. HIF-1 consists of two subunits, HIF-1 alpha and the aryl hydrocarbon receptor nuclear translocator (ARNT). Whereas hypoxia prevents ubiquitination and proteasomal degradation of HIF-1 alpha, ARNT expression is thought to be oxygen-independent. We and others previously showed that ARNT is indispensable for HIF-1 DNA-binding and transactivation function. To examine the requirement of ARNT for accumulation and nuclear translocation of HIF-1 alpha in hypoxia, we used ARNT-mutant mouse hepatoma and ARNT-deficient embryonic stem cells. As shown by immunofluorescence, HIF-1 alpha accumulation in the nucleus of hypoxic cells did not require ARNT, demonstrating that nuclear translocation is intrinsic to HIF-1 alpha. During biochemical separation, both HIF-1 alpha and ARNT tend to leak from the nuclei in the absence of the corresponding subunit, suggesting that heterodimerization is required for stable association within the nuclear compartment. Nuclear stabilization of the heterodimer might also explain the hypoxically increased total cellular ARNT levels observed in some of the cell lines examined.

Hypoxia-inducible factor-1 (HIF-1) is a master regulator of mammalian oxygen homeostasis. HIF-1 consists of two subunits, HIF-1 alpha and the aryl hydrocarbon receptor nuclear translocator (ARNT). Whereas hypoxia prevents ubiquitination and proteasomal degradation of HIF-1 alpha, ARNT expression is thought to be oxygen-independent. We and others previously showed that ARNT is indispensable for HIF-1 DNA-binding and transactivation function. To examine the requirement of ARNT for accumulation and nuclear translocation of HIF-1 alpha in hypoxia, we used ARNT-mutant mouse hepatoma and ARNT-deficient embryonic stem cells. As shown by immunofluorescence, HIF-1 alpha accumulation in the nucleus of hypoxic cells did not require ARNT, demonstrating that nuclear translocation is intrinsic to HIF-1 alpha. During biochemical separation, both HIF-1 alpha and ARNT tend to leak from the nuclei in the absence of the corresponding subunit, suggesting that heterodimerization is required for stable association within the nuclear compartment. Nuclear stabilization of the heterodimer might also explain the hypoxically increased total cellular ARNT levels observed in some of the cell lines examined.

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Additional indexing

Item Type:Book Section, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2000
Deposited On:11 Feb 2008 12:23
Last Modified:05 Apr 2016 12:18
Publisher:Kluwer
Series Name:Advances in Experimental Medicine and Biology
Number:475
ISSN:0065-2598
ISBN:978-0-306-46367-9 (P) 978-0-306-46825-4 (E)
Publisher DOI:10.1007/0-306-46825-5_9
Related URLs:http://www.springer.com/biomed/neuroscience/book/978-0-306-46367-9
PubMed ID:10849651

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