XPKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells

William J. Israelsen, Talya L. Dayton, Shawn M. Davidson, Brian P. Fiske, Aaron M. Hosios, Gary Bellinger, Jie Li, Yimin Yu, Mika Sasaki, James W. Horner, Laura N. Burga, Jianxin Xie, Michael J. Jurczak, Ronald A. Depinho, Clary B. Clish, Tyler Jacks, Richard G. Kibbey, Gerburg M. Wulf, Dolores Di Vizio, Gordon MillsLewis C. Cantley, Matthew G. Vander Heiden

Research output: Contribution to journalArticle

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Abstract

The pyruvate kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in a Brca1-loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and no detectable pyruvate kinase expression in proliferating cells. This suggests that PKM2 is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, whereas nonproliferating tumor cells require active pyruvate kinase. Consistent with these findings, variable PKM2 expression and heterozygous PKM2 mutations are found in human tumors. These data suggest that regulation of PKM2 activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells. PaperClip

Original languageEnglish (US)
JournalCell
Volume155
Issue number2
DOIs
StatePublished - Oct 10 2013
Externally publishedYes

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Pyruvate Kinase
Tumors
Protein Isoforms
Cells
Neoplasms
Breast Neoplasms
Cell proliferation
Metabolism
Alleles
Cell Proliferation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Israelsen, W. J., Dayton, T. L., Davidson, S. M., Fiske, B. P., Hosios, A. M., Bellinger, G., ... Vander Heiden, M. G. (2013). XPKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell, 155(2). https://doi.org/10.1016/j.cell.2013.09.025

XPKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. / Israelsen, William J.; Dayton, Talya L.; Davidson, Shawn M.; Fiske, Brian P.; Hosios, Aaron M.; Bellinger, Gary; Li, Jie; Yu, Yimin; Sasaki, Mika; Horner, James W.; Burga, Laura N.; Xie, Jianxin; Jurczak, Michael J.; Depinho, Ronald A.; Clish, Clary B.; Jacks, Tyler; Kibbey, Richard G.; Wulf, Gerburg M.; Di Vizio, Dolores; Mills, Gordon; Cantley, Lewis C.; Vander Heiden, Matthew G.

In: Cell, Vol. 155, No. 2, 10.10.2013.

Research output: Contribution to journalArticle

Israelsen, WJ, Dayton, TL, Davidson, SM, Fiske, BP, Hosios, AM, Bellinger, G, Li, J, Yu, Y, Sasaki, M, Horner, JW, Burga, LN, Xie, J, Jurczak, MJ, Depinho, RA, Clish, CB, Jacks, T, Kibbey, RG, Wulf, GM, Di Vizio, D, Mills, G, Cantley, LC & Vander Heiden, MG 2013, 'XPKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells', Cell, vol. 155, no. 2. https://doi.org/10.1016/j.cell.2013.09.025
Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G et al. XPKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell. 2013 Oct 10;155(2). https://doi.org/10.1016/j.cell.2013.09.025
Israelsen, William J. ; Dayton, Talya L. ; Davidson, Shawn M. ; Fiske, Brian P. ; Hosios, Aaron M. ; Bellinger, Gary ; Li, Jie ; Yu, Yimin ; Sasaki, Mika ; Horner, James W. ; Burga, Laura N. ; Xie, Jianxin ; Jurczak, Michael J. ; Depinho, Ronald A. ; Clish, Clary B. ; Jacks, Tyler ; Kibbey, Richard G. ; Wulf, Gerburg M. ; Di Vizio, Dolores ; Mills, Gordon ; Cantley, Lewis C. ; Vander Heiden, Matthew G. / XPKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. In: Cell. 2013 ; Vol. 155, No. 2.
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