<br>蛋白激酶导致前 mRNA 加工的致癌失调：挑战和治疗机遇,The FEBS Journal

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蛋白激酶导致前 mRNA 加工的致癌失调：挑战和治疗机遇
The FEBS Journal ( IF 5.5 ) Pub Date : 2021-06-06 , DOI: 10.1111/febs.16057
Chiara Naro _{1,

2} , Pamela Bielli _{3,

4} , Claudio Sette _{1,

4}

Affiliation

选择性剪接和聚腺苷酸化代表了前 mRNA 加工的两个主要步骤，确保了正确的基因表达和人类转录组的多样化。这些过程的放松管制会导致与人类癌症的发生、进展和进化有关的致癌程序，这通常会导致对现有疗法产生耐药性。另一方面，癌细胞经常增加其转录速率并产生转录成瘾，这对前 mRNA 加工机制造成了很高的压力，并建立了治疗上可利用的脆弱性。蛋白激酶的三个主要家族在微调前 mRNA 加工机制中发挥着重要作用：丝氨酸精氨酸蛋白激酶 (SRPK)、CDC 样激酶 (CLK) 和细胞周期蛋白依赖性激酶 (CDK)。这些激酶磷酸化参与新生转录本切割和聚腺苷酸化的 RNA 聚合酶、剪接因子和调节蛋白。 SRPKs、CLKs 和 CDKs 的活性可以在癌细胞中发生改变，并且抑制它们可以发挥抗癌作用。在这篇综述中，我们描述了有关这些主题的主要发现，并讨论了开发针对剪接因子激酶的治疗方法的挑战和机遇。

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Oncogenic dysregulation of pre-mRNA processing by protein kinases: challenges and therapeutic opportunities

Alternative splicing and polyadenylation represent two major steps in pre-mRNA-processing, which ensure proper gene expression and diversification of human transcriptomes. Deregulation of these processes contributes to oncogenic programmes involved in the onset, progression and evolution of human cancers, which often result in the acquisition of resistance to existing therapies. On the other hand, cancer cells frequently increase their transcriptional rate and develop a transcriptional addiction, which imposes a high stress on the pre-mRNA-processing machinery and establishes a therapeutically exploitable vulnerability. A prominent role in fine-tuning pre-mRNA-processing mechanisms is played by three main families of protein kinases: serine arginine protein kinase (SRPK), CDC-like kinase (CLK) and cyclin-dependent kinase (CDK). These kinases phosphorylate the RNA polymerase, splicing factors and regulatory proteins involved in cleavage and polyadenylation of the nascent transcripts. The activity of SRPKs, CLKs and CDKs can be altered in cancer cells, and their inhibition was shown to exert anticancer effects. In this review, we describe key findings that have been reported on these topics and discuss challenges and opportunities of developing therapeutic approaches targeting splicing factor kinases.

更新日期：2021-06-06

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