title: MCM proteins are negative regulators of hypoxia-inducible factor 1.
abstract: 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 O(2)-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.
authors.affiliation: Graduate Training Program in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Maimon E
authors.initials: ME
authors.lastname: Hubbi
authors.forename: Weibo
authors.initials: W
authors.lastname: Luo
authors.forename: Jin H
authors.initials: JH
authors.lastname: Baek
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000502:physiology*; D002460:Cell Line; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism; D014158:Transcription, Genetic; D054875:Ubiquitination
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D010100:Oxygen