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: Sophia Y Lunt, Vinayak Muralidhar, Aaron M Hosios, William J Israelsen, Dan Y Gui, Lauren Newhouse, Martin Ogrodzinski, Vivian Hecht, Kali Xu, Paula N Marín Acevedo, Daniel P Hollern, Gary Bellinger, Talya L Dayton, Stefan Christen, Ilaria Elia, Anh T Dinh, Gregory Stephanopoulos, Scott R Manalis, Michael B Yaffe, Eran R Andrechek, Sarah-Maria Fendt, Matthew G Vander Heiden
• Journal: Molecular cell (Mol Cell) Vol. 57 Issue 1 Pg. 95-107 (Jan 08 2015) ISSN: 1097-4164 [Electronic] United States
• PMID: 25482511 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Nucleotides
• DNA
• Pyruvate Kinase

Topics

• Animals
• Cell Cycle (genetics)
• Cell Proliferation
• DNA (biosynthesis)
• Embryo, Mammalian
• Fibroblasts (cytology, metabolism)
• Gene Expression Regulation
• Metabolic Networks and Pathways (genetics)
• Metabolome (genetics)
• Mice
• Mice, Knockout
• Nucleotides (metabolism)
• Primary Cell Culture
• Pyruvate Kinase (deficiency, genetics)
• Signal Transduction