Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation

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 & 2 others Sarah Maria Fendt, Matthew G. Vander Heiden

    Research output: Contribution to journalArticle

    • 49 Citations

    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.

    Original languageEnglish (US)
    Pages (from-to)95-107
    Number of pages13
    JournalMolecular Cell
    Volume57
    Issue number1
    DOIs
    StatePublished - Jan 8 2015

    Profile

    Pyruvate Kinase
    Protein Isoforms
    Nucleotides
    Cell Proliferation
    DNA
    Thymine
    Cell Aging
    Thymidine
    Cell Differentiation
    Cell Cycle
    Gene Expression
    Neoplasms

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

    Cite this

    Lunt, S. Y., Muralidhar, V., Hosios, A. M., Israelsen, W. J., Gui, D. Y., Newhouse, L., ... Vander Heiden, M. G. (2015). Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. Molecular Cell, 57(1), 95-107. DOI: 10.1016/j.molcel.2014.10.027

    Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. / Lunt, Sophia Y.; Muralidhar, Vinayak; Hosios, Aaron M.; Israelsen, William J.; Gui, Dan Y.; Newhouse, Lauren; Ogrodzinski, Martin; Hecht, Vivian; Xu, Kali; Acevedo, Paula N Marín; Hollern, Daniel P.; Bellinger, Gary; Dayton, Talya L.; Christen, Stefan; Elia, Ilaria; Dinh, Anh T.; Stephanopoulos, Gregory; Manalis, Scott R.; Yaffe, Michael B.; Andrechek, Eran R.; Fendt, Sarah Maria; Vander Heiden, Matthew G.

    In: Molecular Cell, Vol. 57, No. 1, 08.01.2015, p. 95-107.

    Research output: Contribution to journalArticle

    Lunt, SY, Muralidhar, V, Hosios, AM, Israelsen, WJ, Gui, DY, Newhouse, L, Ogrodzinski, M, Hecht, V, Xu, K, Acevedo, PNM, Hollern, DP, Bellinger, G, Dayton, TL, Christen, S, Elia, I, Dinh, AT, Stephanopoulos, G, Manalis, SR, Yaffe, MB, Andrechek, ER, Fendt, SM & Vander Heiden, MG 2015, 'Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation' Molecular Cell, vol 57, no. 1, pp. 95-107. DOI: 10.1016/j.molcel.2014.10.027
    Lunt SY, Muralidhar V, Hosios AM, Israelsen WJ, Gui DY, Newhouse L et al. Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. Molecular Cell. 2015 Jan 8;57(1):95-107. Available from, DOI: 10.1016/j.molcel.2014.10.027

    Lunt, Sophia Y.; Muralidhar, Vinayak; Hosios, Aaron M.; Israelsen, William J.; Gui, Dan Y.; Newhouse, Lauren; Ogrodzinski, Martin; Hecht, Vivian; Xu, Kali; Acevedo, Paula N Marín; Hollern, Daniel P.; Bellinger, Gary; Dayton, Talya L.; Christen, Stefan; Elia, Ilaria; Dinh, Anh T.; Stephanopoulos, Gregory; Manalis, Scott R.; Yaffe, Michael B.; Andrechek, Eran R.; Fendt, Sarah Maria; Vander Heiden, Matthew G. / Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation.

    In: Molecular Cell, Vol. 57, No. 1, 08.01.2015, p. 95-107.

    Research output: Contribution to journalArticle

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    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.",
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