Modulation of M2-type pyruvate kinase activity by the cytoplasmic PML tumor suppressor protein.
The promyelocytic leukemia (PML) tumor suppressor protein accumulates in PML nuclear bodies (PML-NBs), and can induce growth arrest, cellular senescence and apoptosis. PML has also been localized in the cytoplasm, although its function in this localization remains elusive. A general property of primary cancers is their high glycolytic rate which results from increased glucose consumption. However, the mechanism by which cancer cells up-regulate glycolysis is not well understood. Here, we have shown that cytoplasmic PML (cPML) directly interacts with M2-type pyruvate kinase (PKM2), a key regulator of carbon fate. PKM2 determines the proportion of carbons derived from glucose that are used for glycolytic energy production. Over-expression of PML-2KA mutant in the cytoplasm, which was generated by mutagenesis of the nuclear localization signals of PML, in MCF-7 breast cancer cells suppressed PKM2 activity and the accumulation of lactate. PKM2 exists in either an active tetrameric form which has high affinity for its substrate phosphoenolpyruvate (PEP) or a less active dimeric form which has low affinity for its substrate. Over-expression of PML-2KA suppressed the activity of the tetrameric form of PKM2, but not the dimeric form. Our findings suggest that cPML plays a role in tumor metabolism through its interaction with PKM2.
Shimada
Nobukazu
N
Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
Shinagawa
Toshie
T
Ishii
Shunsuke
S
D000818:Animals; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D011770:Pyruvate Kinase