The role of KRAS splice variants in cancer biology.
The role of KRAS splice variants in cancer biology.
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DOI：
10.3389/fcell.2022.1033348
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发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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三种哺乳动物RAS基因（HRAS、NRAS和KRAS）编码在癌症生物学中起核心作用的四种蛋白质。其中，KRAS在人类癌症中的突变频率高于任何其他癌基因。KRAS的前mRNA被选择性剪接以产生两种产物KRAS4A和KRAS4B，其在各自的C末端的膜靶向序列上不同。值得注意的是，当KRAS被外显子2或3中的突变组成性激活时，KRAS4A和KRAS4B都是致癌的。KRAS4B是研究最多的癌蛋白，而KRAS4A研究不足，直到最近才被认为相对不重要。新兴的工作已经证实了KRAS4A在癌症中的表达，并发现了剪接变体的非重叠功能。其中最清楚地证明的是KRAS 4A对己糖激酶1的直接调节，这表明KRAS突变型肿瘤的代谢脆弱性可能部分取决于剪接变体的相对表达。本综述的目的是解决KRAS剪接变异体的最相关的特征和差异功能，因为它们与癌症的发病和进展有关。
The three mammalian RAS genes (HRAS, NRAS and KRAS) encode four proteins that play central roles in cancer biology. Among them, KRAS is mutated more frequently in human cancer than any other oncogene. The pre-mRNA of KRAS is alternatively spliced to give rise to two products, KRAS4A and KRAS4B, which differ in the membrane targeting sequences at their respective C-termini. Notably, both KRAS4A and KRAS4B are oncogenic when KRAS is constitutively activated by mutation in exon 2 or 3. Whereas KRAS4B is the most studied oncoprotein, KRAS4A is understudied and until recently considered relatively unimportant. Emerging work has confirmed expression of KRAS4A in cancer and found non-overlapping functions of the splice variants. The most clearly demonstrated of these is direct regulation of hexokinase 1 by KRAS4A, suggesting that the metabolic vulnerabilities of KRAS-mutant tumors may be determined in part by the relative expression of the splice variants. The aim of this review is to address the most relevant characteristics and differential functions of the KRAS splice variants as they relate to cancer onset and progression.