Gil-Bernabé Ana M, Romero Francisco, Limón-Mortés M Cristina, Tortolero María
Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, Apdo. 1095, 41080 Sevilla, Spain.
Mol Cell Biol. 2006 Jun;26(11):4017-27. doi: 10.1128/MCB.01904-05.
Sister chromatid segregation is triggered at the metaphase-to-anaphase transition by the activation of the protease separase. For most of the cell cycle, separase activity is kept in check by its association with the inhibitory chaperone securin. Activation of separase occurs at anaphase onset, when securin is targeted for destruction by the anaphase-promoting complex or cyclosome E3 ubiquitin protein ligase. This results in the release of the cohesins from chromosomes, which in turn allows the segregation of sister chromatids to opposite spindle poles. Here we show that human securin (hSecurin) forms a complex with enzymatically active protein phosphatase 2A (PP2A) and that it is a substrate of the phosphatase, both in vitro and in vivo. Treatment of cells with okadaic acid, a potent inhibitor of PP2A, results in various hyperphosphorylated forms of hSecurin which are extremely unstable, due to the action of the Skp1/Cul1/F-box protein complex ubiquitin ligase. We propose that PP2A regulates hSecurin levels by counteracting its phosphorylation, which promotes its degradation. Misregulation of this process may lead to the formation of tumors, in which overproduction of hSecurin is often observed.
姐妹染色单体的分离是由蛋白酶分离酶的激活在中期到后期的转变过程中触发的。在细胞周期的大部分时间里，分离酶的活性通过与抑制性伴侣蛋白securin的结合而受到抑制。分离酶的激活发生在后期开始时，此时securin被后期促进复合物或细胞周期体E3泛素蛋白连接酶靶向破坏。这导致黏连蛋白从染色体上释放，进而使得姐妹染色单体分离到纺锤体的相反两极。在这里我们表明，人类securin（hSecurin）与具有酶活性的蛋白磷酸酶2A（PP2A）形成复合物，并且在体外和体内它都是该磷酸酶的底物。用冈田酸（一种PP2A的强效抑制剂）处理细胞，会导致hSecurin出现各种过度磷酸化形式，由于Skp1/Cul1/F-box蛋白复合物泛素连接酶的作用，这些过度磷酸化形式极其不稳定。我们提出，PP2A通过抵消hSecurin的磷酸化来调节其水平，而磷酸化会促进其降解。这个过程的调控异常可能导致肿瘤的形成，在肿瘤中经常观察到hSecurin的过度产生。
