Tuning of alternative splicing--switch from proto-oncogene to tumor suppressor.
Tuning of alternative splicing--switch from proto-oncogene to tumor suppressor.
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DOI：
10.7150/ijbs.5194
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发表时间：
2013
影响因子：
9.2
通讯作者：
Kazansky AV
中科院分区：
文献类型：
--
作者：
Shchelkunova A;Ermolinsky B;Boyle M;Mendez I;Lehker M;Martirosyan KS;Kazansky AV
STAT5B是STAT家族中的一个特殊成员，与前列腺癌的进展密切相关。虽然STAT5B的完整形式被认为促进了肿瘤的进展，但自然产生的截短的异构体起到了肿瘤抑制的作用。我们以前证明了截短的STAT5是通过插入选择性剪接的外显子而产生的，并导致了早期终止密码子的引入。目前针对STAT蛋白的方法主要是通过抑制STAT的功能结构域，如DNA结合、协同结合(蛋白质-蛋白质相互作用)、二聚化和磷酸化等来抑制STAT蛋白的作用，从而抑制STAT蛋白的原癌功能和肿瘤抑制功能。在这份报告中，我们开发了一种新的方法，旨在抑制全长STAT5B(一种原癌基因)的表达，同时增强STAT5∆B(一种肿瘤抑制因子)的表达。我们已经证明了使用空间阻断剪接开关寡核苷酸(SSO)和目标外显子-内含子边界的互补序列来增强替代内含子/外显子保留(高达10%)的可行性。通过细胞增殖和克隆形成实验验证了内含子/外显子比例调节的功能效果。新的方案应用了特定的空间阻断剪接开关寡核苷酸，为抗肿瘤治疗以及改变其他STAT蛋白的功能能力打开了机会。
STAT5B, a specific member of the STAT family, is intimately associated with prostate tumor progression. While the full form of STAT5B is thought to promote tumor progression, a naturally occurring truncated isoform acts as a tumor suppressor. We previously demonstrated that truncated STAT5 is generated by insertion of an alternatively spliced exon and results in the introduction of an early termination codon. Present approaches targeting STAT proteins based on inhibition of functional domains of STAT's, such as DNA-binding, cooperative binding (protein-protein interaction), dimerization and phosphorylation will halt the action of the entire gene, both the proto-oncogenic and tumor suppressor functions of Stat5B. In this report we develop a new approach aimed at inhibiting the expression of full-length STAT5B (a proto-oncogene) while simultaneously enhancing the expression of STAT5∆B (a tumor suppressor). We have demonstrated the feasibility of using steric-blocking splice-switching oligonucleotides (SSOs) with a complimentary sequence to the targeted exon-intron boundary to enhance alternative intron/exon retention (up to 10%). The functional effect of the intron/exon proportional tuning was validated by cell proliferation and clonogenic assays. The new scheme applies specific steric-blocking splice-switching oligonucleotides and opens an opportunity for anti-tumor treatment as well as for the alteration of functional abilities of other STAT proteins.
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影响因子：
8
作者：
Morcinek, JC;Weisser, C;Wellbrock, C
通讯作者：
Wellbrock, C
影响因子：
12.4
作者：
Roberts, Jennifer;Palma, Enzo;Kole, Ryszard
通讯作者：
Kole, Ryszard
影响因子：
4.7
作者：
Chen, HZ;Ye, DF;Lu, WG
通讯作者：
Lu, WG
影响因子：
9.8
作者：
Hua, Yimin;Vickers, Timothy A;Baker, Brenda F;Bennett, C Frank;Krainer, Adrian R
通讯作者：
Krainer, Adrian R
靶向ATM的反义寡脱氧核苷酸增强裸鼠喉鳞状细胞癌的凋亡
DOI：
10.1186/1756-9966-30-43
发表时间：
2011-04-17
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Feng J;Zou J;Li L;Zhao Y;Liu S
通讯作者：
Liu S