title: Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation.
abstract: Metabolic regulation influences cell proliferation. The influence of pyruvate kinase isoforms on tumor cells has been extensively studied, but whether PKM2 is required for normal cell proliferation is unknown. We examine how PKM2 deletion affects proliferation and metabolism in nontransformed, nonimmortalized PKM2-expressing primary cells. We find that deletion of PKM2 in primary cells results in PKM1 expression and proliferation arrest. PKM1 expression, rather than PKM2 loss, is responsible for this effect, and proliferation arrest cannot be explained by cell differentiation, senescence, death, changes in gene expression, or prevention of cell growth. Instead, PKM1 expression impairs nucleotide production and the ability to synthesize DNA and progress through the cell cycle. Nucleotide biosynthesis is limiting, as proliferation arrest is characterized by severe thymidine depletion, and supplying exogenous thymine rescues both nucleotide levels and cell proliferation. Thus, PKM1 expression promotes a metabolic state that is unable to support DNA synthesis.
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Sophia Y
authors.initials: SY
authors.lastname: Lunt
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard-MIT Health Sciences and Technology Division, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Vinayak
authors.initials: V
authors.lastname: Muralidhar
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Hosios
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Israelsen
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Dan Y
authors.initials: DY
authors.lastname: Gui
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Newhouse
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Ogrodzinski
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Hecht
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Kali
authors.initials: K
authors.lastname: Xu
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Paula N Marín
authors.initials: PN
authors.lastname: Acevedo
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Hollern
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Bellinger
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Talya L
authors.initials: TL
authors.lastname: Dayton
authors.affiliation: Vesalius Research Center, VIB, 3000 Leuven, Belgium; Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Christen
authors.affiliation: Vesalius Research Center, VIB, 3000 Leuven, Belgium; Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Elia
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Anh T
authors.initials: AT
authors.lastname: Dinh
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Stephanopoulos
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Manalis
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Yaffe
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Eran R
authors.initials: ER
authors.lastname: Andrechek
authors.affiliation: Vesalius Research Center, VIB, 3000 Leuven, Belgium; Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Sarah-Maria
authors.initials: SM
authors.lastname: Fendt
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: mvh@mit.edu.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D004247:DNA / Q000096:biosynthesis; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D053858:Metabolic Networks and Pathways / Q000235:genetics; D055442:Metabolome / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009711:Nucleotides / Q000378:metabolism*; D061251:Primary Cell Culture; D011770:Pyruvate Kinase / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D009711:Nucleotides; D004247:DNA; D011770:Pyruvate Kinase