Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Polyclinic, Palermo, Italy.
Associazione Siciliana per la Lotta contro i Tumori (ASLOT), Palermo, Italy.
J Cell Physiol. 2018 Nov;233(11):8482-8498. doi: 10.1002/jcp.26786. Epub 2018 May 24.
The Bcl-2 family, which plays important roles in controlling cancer development, is divided into antiapoptotic and proapoptotic members. The change in the balance between these members governs the life and death of the cells. Mcl-1 is an antiapoptotic member of this family and its distribution in normal and cancerous tissues strongly differs from that of Bcl-2. In human cancers, where upregulation of antiapoptotic proteins is common, Mcl-1 expression is regulated independent of Bcl-2 and its inhibition promotes senescence, a major barrier to tumorigenesis. Cancer chemotherapy determines various kinds of responses, such as senescence and autophagy; however, the ideal response to chemotherapy is apoptosis. Mcl-1 is a potent oncogene that is regulated at the transcriptional, posttranscriptional, and posttranslational levels. Mcl-1 is a short-lived protein that, in the NH2 terminal region, contains sites for posttranslational regulation that can lead to proteasomal degradation. The USP9X Mcl-1 deubiquitinase regulates Mcl-1 and the levels of these two proteins are strongly correlated. Mcl-1 has three splicing variants (the antiapoptotic protein Mcl-1L and the proapoptotic proteins Mcl-1S and Mcl-1ES), each contributing toward apoptosis regulation. In cancers responsible for the most deaths in the world, the presence of Mcl-1 is associated with malignant cell growth and evasion of apoptosis. Mcl-1 is also one of the key regulators of cancer stem cells' self-renewal that contributes to tumor survival. A great number of indirect and selective Mcl-1 inhibitors have been produced and some of these have shown efficacy in several clinical trials. Thus, therapeutic manipulation of Mcl-1 can be a useful strategy to combat cancer.
Bcl-2 家族在控制癌症发展中发挥着重要作用，它分为抗凋亡和促凋亡成员。这些成员之间的平衡变化决定了细胞的生死。Mcl-1 是该家族的抗凋亡成员，其在正常组织和癌组织中的分布与 Bcl-2 有很大不同。在人类癌症中，抗凋亡蛋白的上调很常见，Mcl-1 的表达调节独立于 Bcl-2，其抑制促进衰老，这是肿瘤发生的主要障碍。癌症化疗决定了各种反应，如衰老和自噬；然而，理想的化疗反应是凋亡。Mcl-1 是一个强有力的癌基因，它在转录、转录后和翻译后水平受到调节。Mcl-1 是一种短寿命的蛋白质，在 NH2 末端区域含有翻译后调节的位点，这可能导致蛋白酶体降解。USP9X Mcl-1 去泛素化酶调节 Mcl-1，这两种蛋白质的水平密切相关。Mcl-1 有三个剪接变体（抗凋亡蛋白 Mcl-1L 和促凋亡蛋白 Mcl-1S 和 Mcl-1ES），每个变体都有助于凋亡调节。在世界上导致死亡人数最多的癌症中，Mcl-1 的存在与恶性细胞生长和逃避凋亡有关。Mcl-1 也是癌症干细胞自我更新的关键调节因子之一，有助于肿瘤存活。已经产生了大量的间接和选择性 Mcl-1 抑制剂，其中一些在几项临床试验中显示出疗效。因此，对 Mcl-1 的治疗性操纵可能是对抗癌症的一种有用策略。
