The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis.
The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis.
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DOI：
10.1158/0008-5472.can-12-3082
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发表时间：
2013-05-01
期刊：
影响因子：
11.2
通讯作者：
Blackburn EH
中科院分区：
文献类型：
--
作者：
Listerman I;Sun J;Gazzaniga FS;Lukas JL;Blackburn EH
TERT （TERT）是端粒酶的催化蛋白亚基，受到许多不同剪接事件的影响，但这些剪接变异体的调控和功能尚不清楚。全长hTERT包括编码逆转录酶活性、RNA结合和其他功能的保守结构域。被称为α+β -或β-缺失的主要剪接变体在干细胞和癌细胞中高度表达，它编码缺乏大部分逆转录酶结构域的截断蛋白，但保留已知的RNA结合基序。在乳腺癌细胞组中，我们发现β-缺失是表达最高的hTERT转录本。该转录物的剪接受剪接调节因子SRSF11、HNRNPH2和HNRNPL控制，β-缺失转录物变体与细胞中的多核糖体相关。当异位过表达时，β-缺失蛋白竞争与hTR (TERC) RNA结合，从而抑制内源性端粒酶活性。过度表达的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凋亡。我们的研究结果表明，一个主要的hTERT剪接变体可以赋予癌细胞独立于端粒维持的生长优势，这表明hTERT对癌症病理生理有多种贡献。
hTERT (TERT), 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 hTR (TERC) RNA, thereby inhibiting endogenous telomerase activity. Overexpressed β-deletion protein localized to the nucleus and mitochondria and it 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 hTERT makes multiple contributions to cancer pathophysiology.