剪接因子 hnRNPA1 调控 LOXL2 的可变剪接，增强 LOXL2Δ13 的产生。
Splicing factor hnRNPA1 regulates alternative splicing of LOXL2 to enhance the production of LOXL2Δ13.
机构信息
Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China.
Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China.
出版信息
J Biol Chem. 2024 Jul;300(7):107414. doi: 10.1016/j.jbc.2024.107414. Epub 2024 May 27.
Lysyl oxidase-like 2 (LOXL2) is a member of the lysyl oxidase family and has the ability to catalyze the cross-linking of extracellular matrix collagen and elastin. High expression of LOXL2 is related to tumor cell proliferation, invasion, and metastasis. LOXL2 contains 14 exons. Previous studies have found that LOXL2 has abnormal alternative splicing and exon skipping in a variety of tissues and cells, resulting in a new alternatively spliced isoform denoted LOXL2Δ13. LOXL2Δ13 lacks LOXL2WT exon 13, but its encoded protein has greater ability to induce tumor cell proliferation, invasion, and metastasis. However, the molecular events that produce LOXL2Δ13 are still unclear. In this study, we found that overexpression of the splicing factor hnRNPA1 in cells can regulate the alternative splicing of LOXL2 and increase the expression of LOXL2Δ13. The exonic splicing silencer exists at the 3' splice site and 5' splice site of LOXL2 exon 13. HnRNPA1 can bind to the exonic splicing silencer and inhibit the inclusion of exon 13. The RRM domain of hnRNPA1 and phosphorylation of hnRNPA1 at S91 and S95 are important for the regulation of LOXL2 alternative splicing. These results show that hnRNPA1 is a splicing factor that enhances the production of LOXL2Δ13.
赖氨酰氧化酶样蛋白 2（LOXL2）是赖氨酰氧化酶家族的一员，具有催化细胞外基质胶原和弹性蛋白交联的能力。LOXL2 的高表达与肿瘤细胞的增殖、侵袭和转移有关。LOXL2 包含 14 个外显子。先前的研究发现，LOXL2 在多种组织和细胞中存在异常的选择性剪接和外显子跳跃，导致新的选择性剪接异构体 LOXL2Δ13。LOXL2Δ13 缺乏 LOXL2WT 外显子 13，但它编码的蛋白质具有更强的诱导肿瘤细胞增殖、侵袭和转移的能力。然而，产生 LOXL2Δ13 的分子事件仍不清楚。在本研究中，我们发现细胞中剪接因子 hnRNPA1 的过表达可以调节 LOXL2 的选择性剪接，增加 LOXL2Δ13 的表达。LOXL2 外显子 13 的 3'剪接位点和 5'剪接位点存在外显子剪接沉默子。hnRNPA1 可以与外显子剪接沉默子结合，抑制外显子 13 的包含。hnRNPA1 的 RRM 结构域和 hnRNPA1 在 S91 和 S95 位的磷酸化对 LOXL2 选择性剪接的调节很重要。这些结果表明，hnRNPA1 是一种增强 LOXL2Δ13 产生的剪接因子。
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