Department of Hematology and Oncology of Children's Medical Center, The First Affiliated Hospital of Hunan Normal University/Hunan Provincial People's Hospital, Changsha, Hunan, China.
J Cell Biochem. 2018 Nov;119(11):9217-9228. doi: 10.1002/jcb.27189. Epub 2018 Aug 13.
Burkitt lymphoma is one of the most common lymphatic system cancers with poor outcome in adult patients. p53-induced apoptosis is a critical signaling for preventing tumor development. Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53. However, p53 is frequently mutated in Burkitt lymphoma, which gains novel oncogenic properties. Recently, the p53 family member, p63, became an attractive gene for the therapeutic strategies for patients with cancer. Therefore, we investigated the role of iASPP in the transactivation domain p63 (TAp63)-dependent cell proliferation inhibition in Burkitt lymphoma. We verified that the oncogenic effect of iASPP on Burkitt lymphoma is TAp63 dependent rather than p53 and confirmed that the interaction between CDK1 and iASPP enhanced the inhibitory effect of iASPP on p53 and TAp63. An online tool predicated that miR-129 might bind to 3'-untranslated region of iASPP and CDK1. We revealed that miR-129 acted as a tumor suppressor by inhibiting cancer cell proliferation and inhibiting CDK1 and iASPP via direct binding. An miR-129 inhibitor increased nucleus iASPP and decreased nucleus p53 and TAp63 levels, which could be reversed by the CDK1 knockdown, indicating that miR-129 might target CDK1 to inhibit iASPP phosphorylation, thus hindering iASPP nucleus localization and its inhibitory effect on p53 and TAp63 protein levels. Taken together, miR-129 could targetedly inhibit the expression of CDK1 and iASPP. CDK1 knockdown inhibits iASPP S84/S113 phosphorylation, thus blocking iASPP nucleus localization, suppressing the inhibitory effect of iASPP on p53 and TAp63, and restoring TAp63-induced proliferation inhibition in Burkitt lymphoma cells.
伯基特淋巴瘤是最常见的淋巴系统癌症之一，成年患者预后不良。p53 诱导的细胞凋亡是防止肿瘤发生的关键信号。细胞周期蛋白 B/细胞周期蛋白依赖性激酶 1（CDK1）磷酸化凋亡刺激蛋白的 p53 抑制剂（iASPP），以促进 iASPP 核定位及其对 p53 的抑制作用。然而，伯基特淋巴瘤中 p53 经常发生突变，从而获得新的致癌特性。最近，p53 家族成员 p63 成为癌症患者治疗策略的一个有吸引力的基因。因此，我们研究了 iASPP 在 p63（TAp63）依赖的细胞增殖抑制中的作用。我们验证了 iASPP 对伯基特淋巴瘤的致癌作用是 TAp63 依赖性的，而不是 p53 依赖性的，并证实 CDK1 和 iASPP 之间的相互作用增强了 iASPP 对 p53 和 TAp63 的抑制作用。在线工具预测 miR-129 可能与 iASPP 和 CDK1 的 3'非翻译区结合。我们揭示了 miR-129 通过直接结合抑制癌症细胞增殖并抑制 CDK1 和 iASPP，从而发挥肿瘤抑制作用。miR-129 抑制剂增加了核 iASPP 并降低了核 p53 和 TAp63 水平，这可以通过 CDK1 敲低来逆转，表明 miR-129 可能通过靶向 CDK1 来抑制 iASPP 磷酸化，从而阻碍 iASPP 核定位及其对 p53 和 TAp63 蛋白水平的抑制作用。总之，miR-129 可以靶向抑制 CDK1 和 iASPP 的表达。CDK1 敲低抑制 iASPP S84/S113 磷酸化，从而阻断 iASPP 核定位，抑制 iASPP 对 p53 和 TAp63 的抑制作用，并恢复 TAp63 诱导的伯基特淋巴瘤细胞增殖抑制。
