title: PP2A-mediated regulation of Ras signaling in G2 is essential for stable quiescence and normal G1 length.
abstract: Quiescence (G0) allows cycling cells to reversibly cease proliferation. A decision to enter quiescence is suspected of occurring early in G1, before the restriction point (R). Surprisingly, we have identified G2 as an interval during which inhibition of the protein phosphatase PP2A results in failure to exhibit stable quiescence. This effect is accompanied by shortening of the ensuing G1. The PP2A subcomplex required for stable G0 contains the B56γ B subunit. After PP2A inhibition in G2, aberrant overexpression of cyclin E occurs during mitosis and is responsible for overriding quiescence. Strikingly, suppression of Ras signaling re-establishes normal cyclin E levels during M and restores G0. These data point to PP2A-B56γ-driven Ras signaling modulation in G2 as essential for suppressing aberrant cyclin E expression during mitosis and thereby achieving normal G0 control. Thus, G2 is an interval during which the length and growth factor dependence of the next G1 interval are established.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Nana
authors.initials: N
authors.lastname: Naetar
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Velmurugan
authors.initials: V
authors.lastname: Soundarapandian
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Larisa
authors.initials: L
authors.lastname: Litovchick
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Kelsey L
authors.initials: KL
authors.lastname: Goguen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Sablina
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Bowman-Colin
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: DeCaprio
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: david_livingston@dfci.harvard.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Livingston
mesh_terms: D002460:Cell Line; D019927:Cyclin E / Q000096:biosynthesis; D016193:G1 Phase / Q000235:genetics*; D016195:G2 Phase / Q000235:genetics*; D006801:Humans; D061986:MCF-7 Cells; D008938:Mitosis / Q000235:genetics; D015689:Oncogene Protein p21(ras) / Q000235:genetics*; D054648:Protein Phosphatase 2 / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D016192:Resting Phase, Cell Cycle / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D019927:Cyclin E; D021122:Protein Subunits; D034741:RNA, Small Interfering; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2; D015689:Oncogene Protein p21(ras)