Department of Oncology, Xiangya Hospital, Central South University, 410008, Changsha, China.
Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Cell Death Dis. 2019 May 16;10(6):385. doi: 10.1038/s41419-019-1621-2.
SE translocation (SET), an inhibitor of protein phosphatase 2A (PP2A), plays important roles in mitosis and possesses oncogenic activity in several types of cancer. However, little is known regarding its regulation. Here we reveal a novel phosphorylation site of SET isoform 1, and we have determined its biological significance in tumorigenesis. We found that the mitotic kinase cyclin-dependent kinase 1 (CDK1) phosphorylates SET isoform 1 in vitro and in vivo at serine 7 during antitubulin drug-induced mitotic arrest and normal mitosis. SET deletion resulted in massive multipolar spindles, chromosome misalignment and missegregation, and centrosome amplification during mitosis. Moreover, mitotic phosphorylation of SET isoform 1 is required for cell migration, invasion, and anchorage-independent growth in vitro and tumorigenesis in xenograft animal models. We further documented that SET phosphorylation affects Akt activity. Collectively, our findings suggest that SET isoform 1 promotes oncogenesis in a mitotic phosphorylation-dependent manner.
SET 易位（SET）是蛋白磷酸酶 2A（PP2A）的抑制剂，在有丝分裂中发挥重要作用，并在多种类型的癌症中具有致癌活性。然而，其调节作用知之甚少。在这里，我们揭示了 SET 同种型 1 的一个新的磷酸化位点，并确定了其在肿瘤发生中的生物学意义。我们发现，有丝分裂激酶周期蛋白依赖性激酶 1（CDK1）在体外和体内在抗微管药物诱导的有丝分裂阻滞和正常有丝分裂过程中磷酸化 SET 同种型 1 的丝氨酸 7 位。SET 缺失导致有丝分裂过程中大量的多极纺锤体、染色体错位和分离、中心体扩增。此外，SET 同种型 1 的有丝分裂磷酸化对于体外细胞迁移、侵袭和无锚定生长以及异种移植动物模型中的肿瘤发生是必需的。我们进一步证明 SET 磷酸化影响 Akt 活性。总之，我们的研究结果表明，SET 同种型 1 通过有丝分裂磷酸化依赖性促进致癌作用。
