title: A new mitochondrial pool of cyclin E, regulated by Drp1, is linked to cell-density-dependent cell proliferation.
abstract: The regulation and function of the crucial cell cycle regulator cyclin E (CycE) remains elusive. Unlike other cyclins, CycE can be uniquely controlled by mitochondrial energetics, the exact mechanism being unclear. Using mammalian cells (in vitro) and Drosophila (in vivo) model systems in parallel, we show that CycE can be directly regulated by mitochondria through its recruitment to the organelle. Active mitochondrial bioenergetics maintains a distinct mitochondrial pool of CycE (mtCycE) lacking a key phosphorylation required for its degradation. Loss of the mitochondrial fission protein dynamin-related protein 1 (Drp1, SwissProt O00429 in humans) augments mitochondrial respiration and elevates the mtCycE pool allowing CycE deregulation, cell cycle alterations and enrichment of stem cell markers. Such CycE deregulation after Drp1 loss attenuates cell proliferation in low-cell-density environments. However, in high-cell-density environments, elevated MEK-ERK signaling in the absence of Drp1 releases mtCycE to support escape of contact inhibition and maintain aberrant cell proliferation. Such Drp1-driven regulation of CycE recruitment to mitochondria might be a mechanism to modulate CycE degradation during normal developmental processes as well as in tumorigenic events.
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Danitra J
authors.initials: DJ
authors.lastname: Parker
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Iyer
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Shikha
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Aida
authors.initials: A
authors.lastname: Moran
authors.affiliation: Department of Cell Development and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Anita B
authors.initials: AB
authors.lastname: Hjelmeland
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Malay Kumar
authors.initials: MK
authors.lastname: Basu
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Runhua
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA kasturi@uab.edu.
authors.forename: Kasturi
authors.initials: K
authors.lastname: Mitra
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D034281:Dynamins; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D014162:Transfection
chemical_list: D019927:Cyclin E; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: Cell cycle; Cell proliferation; Cyclin E; Drp1; Mitochondria