Modulation of M2-type pyruvate kinase activity by the cytoplasmic PML tumor suppressor protein
Modulation of M2-type pyruvate kinase activity by the cytoplasmic PML tumor suppressor protein
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DOI：
10.1111/j.1365-2443.2008.01165.x
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发表时间：
2008-03-01
期刊：
影响因子：
2.1
通讯作者：
Ishii, Shunsuke
中科院分区：
文献类型：
--
作者：
Shimada, Nobukazu;Shinagawa, Toshie;Ishii, Shunsuke
早幼粒细胞白血病（PML）肿瘤抑制蛋白聚集在PML核小体（PML-NB）中，可诱导细胞生长停滞、衰老和凋亡。PML也定位于细胞质中，尽管其在该定位中的功能仍然不清楚。原发性癌症的一般特性是它们的高糖酵解速率，这是由增加的葡萄糖消耗引起的。然而，癌细胞上调糖酵解的机制尚不清楚。在这里，我们已经表明，细胞质PML（cPML）直接与M2型丙酮酸激酶（PKM 2），碳命运的关键调节因子相互作用。PKM 2决定了用于糖酵解能量产生的来自葡萄糖的碳的比例。在MCF-7乳腺癌细胞中，通过突变PML的核定位信号而产生的PML-2KA突变体在细胞质中的过表达抑制PKM 2活性和乳酸的积累。PKM 2以对其底物磷酸烯醇丙酮酸（PEP）具有高亲和力的活性四聚体形式或对其底物具有低亲和力的活性较低的二聚体形式存在。PML-2KA的过表达抑制PKM 2的四聚体形式的活性，但不抑制二聚体形式。我们的研究结果表明，cPML通过与PKM 2的相互作用在肿瘤代谢中发挥作用。
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.