Stapled peptide inhibitors of RAB25 target context-specific phenotypes in cancer.
Stapled peptide inhibitors of RAB25 target context-specific phenotypes in cancer.
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DOI：
10.1038/s41467-017-00888-8
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发表时间：
2017-09-22
影响因子：
16.6
通讯作者：
Moellering RE
中科院分区：
文献类型：
--
作者：
Mitra S;Montgomery JE;Kolar MJ;Li G;Jeong KJ;Peng B;Verdine GL;Mills GB;Moellering RE
最近的证据表明，在特定的细胞环境中，小GTP酶RAB25以及相关的效应蛋白在决定致癌和抗癌表型方面发挥了作用。在这里，我们报告了来自RAB结合FIP家族的全烃稳定多肽的发展，以靶向RAB25。与未修饰的多肽相比，优化后的多肽具有更高的结构稳定性、结合亲和力、细胞通透性和抑制RAB25：FIP复合体的形成。用优化的装订多肽RFP14治疗RAB25致癌的癌细胞株，以RAB25依赖的方式抑制迁移和增殖。相比之下，RFP14治疗增加了RAB25抑制肿瘤的乳腺癌细胞的这些表型。转录谱发现RAB25表达引起显著改变的转录本，用RFP14治疗反对这种表达谱。这些数据验证了第一个针对RAB家族蛋白的细胞活性化学探针，并支持RAB25在调节上下文特定的致癌表型中的作用。RAS家族小分子GTP酶RAB25既能发挥促癌作用，又能发挥抗肿瘤作用。在这里，作者开发了针对RAB25的全烃稳定多肽，并影响癌细胞系中的上下文特异性表型。
Recent evidence has established a role for the small GTPase RAB25, as well as related effector proteins, in enacting both pro-oncogenic and anti-oncogenic phenotypes in specific cellular contexts. Here we report the development of all-hydrocarbon stabilized peptides derived from the RAB-binding FIP-family of proteins to target RAB25. Relative to unmodified peptides, optimized stapled peptides exhibit increased structural stability, binding affinity, cell permeability, and inhibition of RAB25:FIP complex formation. Treatment of cancer cell lines in which RAB25 is pro-oncogenic with an optimized stapled peptide, RFP14, inhibits migration, and proliferation in a RAB25-dependent manner. In contrast, RFP14 treatment augments these phenotypes in breast cancer cells in which RAB25 is tumor suppressive. Transcriptional profiling identified significantly altered transcripts in response to RAB25 expression, and treatment with RFP14 opposes this expression profile. These data validate the first cell-active chemical probes targeting RAB-family proteins and support the role of RAB25 in regulating context-specific oncogenic phenotypes. The Ras-family small GTPase RAB25 can exert both pro- and anti-oncogenic functions. Here, the authors develop all-hydrocarbon stabilized peptides targeting RAB25 and influencing the context-specificity phenotypes in cancer cell lines.
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影响因子：
15
作者：
LaRochelle JR;Cobb GB;Steinauer A;Rhoades E;Schepartz A
通讯作者：
Schepartz A
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
15.9
作者：
Nam, Ki Taek;Lee, Hyuk-Joon;Goldenring, James R.
通讯作者：
Goldenring, James R.
影响因子：
11.8
作者：
Dozynkiewicz, Marta A.;Jamieson, Nigel B.;MacPherson, Iain;Grindlay, Joan;van den Berghe, Peter V. E.;von Thun, Anne;Morton, Jennifer P.;Gourley, Charlie;Timpson, Paul;Nixon, Colin;McKay, Colin J.;Carter, Ross;Strachan, David;Anderson, Kurt;Sansom, Owen J.;Caswell, Patrick T.;Norman, Jim C.
通讯作者：
Norman, Jim C.
DOI：
10.1083/jcb.201109112
发表时间：
2012-01-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Rainero E;Caswell PT;Muller PA;Grindlay J;McCaffrey MW;Zhang Q;Wakelam MJ;Vousden KH;Graziani A;Norman JC
通讯作者：
Norman JC