MCM Proteins Are Negative Regulators of Hypoxia-Inducible Factor 1

MCM proteins are components of a DNA helicase that plays an essential role in DNA replication and cell proliferation. However, MCM proteins are present in excess relative to origins of replication, suggesting they may serve other functions. Decreased proliferation is a fundamental physiological resp...

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Bibliographic Details
Published in:Molecular cell 2011-06, Vol.42 (5), p.700-712
Main Authors: Hubbi, Maimon E., Luo, Weibo, Baek, Jin H., Semenza, Gregg L.
Format: Article
Language:English
Subjects:
Animals
Basic Helix-Loop-Helix Transcription Factors - antagonists & inhibitors
Basic Helix-Loop-Helix Transcription Factors - metabolism
cell cycle
Cell Cycle Proteins - physiology
Cell Line
cell proliferation
cells
DNA helicases
DNA replication
Gene Expression Regulation
HEK293 Cells
Humans
hypoxia
hypoxia-inducible factor 1
Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Mice
NIH 3T3 Cells
Nuclear Proteins - physiology
Oxygen - metabolism
physiological response
proteins
replication origin
transcription (genetics)
Transcription, Genetic
transcriptional activation
Ubiquitination
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Summary:MCM proteins are components of a DNA helicase that plays an essential role in DNA replication and cell proliferation. However, MCM proteins are present in excess relative to origins of replication, suggesting they may serve other functions. Decreased proliferation is a fundamental physiological response to hypoxia in many cell types, and hypoxia-inducible factor 1 (HIF-1) has been implicated in this process. Here, we demonstrate that multiple MCM proteins bind directly to the HIF-1α subunit and synergistically inhibit HIF-1 transcriptional activity via distinct O2-dependent mechanisms. MCM3 inhibits transactivation domain function, whereas MCM7 enhances HIF-1α ubiquitination and proteasomal degradation. HIF-1 activity decreases when quiescent cells re-enter the cell cycle, and this effect is MCM dependent. Exposure to hypoxia leads to MCM2–7 downregulation in diverse cell types. These studies reveal a function of MCM proteins apart from their DNA helicase activity and establish a direct link between HIF-1 and the cell-cycle machinery. [Display omitted] ► Four MCM proteins bind to HIF-1α and inhibit HIF-1 activity ► MCM7 downregulates HIF-1α protein levels ► MCM3 inhibits HIF-1α transactivation function ► Hypoxia and quiescence are associated with MCM downregulation and HIF upregulation
ISSN:1097-2765
1097-4164
1097-4164
DOI:10.1016/j.molcel.2011.03.029