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Mol Cell. 2015 Jan 8;57(1):95-107. doi: 10.1016/j.molcel.2014.10.027. Epub 2014 Dec 4.

Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation.

Author information

1
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.
2
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.
3
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.
4
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
5
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA.
6
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.
7
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
8
Vesalius Research Center, VIB, 3000 Leuven, Belgium; Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
9
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
10
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.
11
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.

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.

PMID:
25482511
PMCID:
PMC4289430
DOI:
10.1016/j.molcel.2014.10.027
[Indexed for MEDLINE]
Free PMC Article

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