Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California, USA.
Cancer Res. 2013 May 1;73(9):2817-28. doi: 10.1158/0008-5472.CAN-12-3082. Epub 2013 Apr 22.
Human telomerase reverse transcriptase (hTERT; the catalytic protein subunit of telomerase) is subjected to numerous alternative splicing events, but the regulation and function of these splice variants is obscure. Full-length hTERT includes conserved domains that encode reverse transcriptase activity, RNA binding, and other functions. The major splice variant termed α+β- or β-deletion is highly expressed in stem and cancer cells, where it codes for a truncated protein lacking most of the reverse transcriptase domain but retaining the known RNA-binding motifs. In a breast cancer cell panel, we found that β-deletion was the hTERT transcript that was most highly expressed. Splicing of this transcript was controlled by the splice regulators SRSF11, HNRNPH2, and HNRNPL, and the β-deletion transcript variant was associated with polyribosomes in cells. When ectopically overexpressed, β-deletion protein competed for binding to telomerase RNA (hTR/TERC), thereby inhibiting endogenous telomerase activity. Overexpressed β-deletion protein localized to the nucleus and mitochondria and protected breast cancer cells from cisplatin-induced apoptosis. Our results reveal that a major hTERT splice variant can confer a growth advantage to cancer cells independent of telomere maintenance, suggesting that hTERT makes multiple contributions to cancer pathophysiology.
人类端粒酶逆转录酶（hTERT；端粒酶的催化蛋白亚基）经历了许多选择性剪接事件，但这些剪接变体的调节和功能尚不清楚。全长 hTERT 包含编码逆转录酶活性、RNA 结合和其他功能的保守结构域。主要的剪接变体称为α+β-或β-缺失，在干细胞和癌细胞中高度表达，它编码一种截断的蛋白质，缺乏大部分逆转录酶结构域，但保留已知的 RNA 结合基序。在乳腺癌细胞系中，我们发现β-缺失是 hTERT 转录本中表达最高的。这种转录本的剪接受剪接调节因子 SRSF11、HNRNPH2 和 HNRNPL 控制，β-缺失转录本变体与细胞中的多核糖体相关。当异位过表达时，β-缺失蛋白与端粒酶 RNA（hTR/TERC）竞争结合，从而抑制内源性端粒酶活性。过表达的β-缺失蛋白定位于细胞核和线粒体，并保护乳腺癌细胞免受顺铂诱导的细胞凋亡。我们的结果表明，一种主要的 hTERT 剪接变体可以赋予癌细胞生长优势，而不依赖于端粒维持，这表明 hTERT 对癌症病理生理学有多种贡献。
