Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, USA.
Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):528-33. doi: 10.1073/pnas.1013214108. Epub 2010 Dec 27.
The serine/threonine Pim kinases are overexpressed in solid cancers and hematologic malignancies and promote cell growth and survival. Here, we find that a novel Pim kinase inhibitor, SMI-4a, or Pim-1 siRNA blocked the rapamycin-sensitive mammalian target of rapamycin (mTORC1) activity by stimulating the phosphorylation and thus activating the mTORC1 negative regulator AMP-dependent protein kinase (AMPK). Mouse embryonic fibroblasts (MEFs) deficient for all three Pim kinases [triple knockout (TKO) MEFs] demonstrated activated AMPK driven by elevated ratios of AMPATP relative to wild-type MEFs. Consistent with these findings, TKO MEFs were found to grow slowly in culture and have decreased rates of protein synthesis secondary to a diminished amount of 5'-cap-dependent translation. Pim-3 expression alone in TKO MEFs was sufficient to reverse AMPK activation, increase protein synthesis, and drive MEF growth similar to wild type. Pim-3 expression was found to markedly increase the protein levels of both c-Myc and the peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), enzymes capable of regulating glycolysis and mitochondrial biogenesis, which were diminished in TKO MEFs. Overexpression of PGC-1α in TKO MEFs elevated ATP levels and inhibited the activation of AMPK. These results demonstrate the Pim kinase-mediated control of energy metabolism and thus regulation of AMPK activity. We identify an important role for Pim-3 in modulating c-Myc and PGC-1α protein levels and cell growth.
丝氨酸/苏氨酸 Pim 激酶在实体瘤和血液恶性肿瘤中过度表达，促进细胞生长和存活。在这里，我们发现一种新型 Pim 激酶抑制剂 SMI-4a 或 Pim-1 siRNA 通过刺激磷酸化从而激活 mTORC1 负调节剂 AMP 依赖的蛋白激酶（AMPK）来阻断雷帕霉素敏感的哺乳动物雷帕霉素靶蛋白（mTORC1）活性。缺乏所有三种 Pim 激酶的小鼠胚胎成纤维细胞（MEF）[三重敲除（TKO）MEF]表现出 AMPK 的激活，这是由相对于野生型 MEF 升高的 AMPATP 比率驱动的。与这些发现一致，TKO MEF 在培养中生长缓慢，并且由于 5'-帽依赖性翻译的量减少，蛋白质合成率降低。仅在 TKO MEF 中表达 Pim-3 足以逆转 AMPK 激活，增加蛋白质合成，并驱动 MEF 生长类似于野生型。发现 Pim-3 表达可显著增加 c-Myc 和过氧化物酶体增殖物激活受体 γ 共激活因子 1α（PGC-1α）的蛋白水平，这两种酶都能够调节糖酵解和线粒体生物发生，在 TKO MEF 中减少。PGC-1α 在 TKO MEF 中的过表达可提高 ATP 水平并抑制 AMPK 的激活。这些结果表明 Pim 激酶介导的能量代谢控制，从而调节 AMPK 活性。我们确定了 Pim-3 在调节 c-Myc 和 PGC-1α 蛋白水平和细胞生长中的重要作用。
