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Cell DOI:10.1016/j.cell.2013.09.025

PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells.

Publication TypeJournal Article
Year of Publication2013
AuthorsIsraelsen, 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, GB, Cantley, LC, Heiden, MGVander
JournalCell
Volume155
Issue2
Pages397-409
Date Published2013 Oct 10
ISSN1097-4172
KeywordsAnimals, Base Sequence, Breast Neoplasms, Exons, Female, Gene Deletion, Gene Knockout Techniques, Heterografts, Humans, Isoenzymes, Mammary Neoplasms, Experimental, Mice, Mice, Inbred C57BL, Models, Molecular, Molecular Sequence Data, Mutagenesis, Mutation, Neoplasm Metastasis, Neoplasm Transplantation, Pyruvate Kinase, RNA Splicing
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.

DOI10.1016/j.cell.2013.09.025
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24120138?dopt=Abstract

Alternate JournalCell
PubMed ID24120138
PubMed Central IDPMC3850755
Grant List5K08CA136983 / CA / NCI NIH HHS / United States
R00 CA131472 / CA / NCI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
R01 CA168653 / CA / NCI NIH HHS / United States
5P01CA117969 / CA / NCI NIH HHS / United States
P01 CA117969 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
P50 CA098258 / CA / NCI NIH HHS / United States
U24 DK059635 / DK / NIDDK NIH HHS / United States
R01GM056203 / GM / NIGMS NIH HHS / United States
R01CA168653 / CA / NCI NIH HHS / United States
5P30CA14051 / CA / NCI NIH HHS / United States
R01DK092606 / DK / NIDDK NIH HHS / United States
P30CA147882 / CA / NCI NIH HHS / United States
K08 CA136983 / CA / NCI NIH HHS / United States
R01 DK092606 / DK / NIDDK NIH HHS / United States
DK059635 / DK / NIDDK NIH HHS / United States
R00CA131472 / CA / NCI NIH HHS / United States
P30 CA147882 / CA / NCI NIH HHS / United States
R01 GM056203 / GM / NIGMS NIH HHS / United States