Cancer‐associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17
Cancer‐associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17
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DOI：
10.1111/febs.15076
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发表时间：
2020-01
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影响因子：
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通讯作者：
Yogesh Srivastava;D. Tan;Vikas Malik;Mingxi Weng;Asif Javed;Vlad Cojocaru;Guangming Wu;Veeramohan Veerap
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作者：
Yogesh Srivastava;D. Tan;Vikas Malik;Mingxi Weng;Asif Javed;Vlad Cojocaru;Guangming Wu;Veeramohan Veerap
对于大多数蛋白质而言，癌症相关错义突变的功能后果尚不清楚。我们之前已经证明，在多能重编程过程中，SOX和Pit - Oct - Unc （POU）家族因子的活性可以通过合理放置的点突变进行切换和增强。在这里，我们查询了癌症突变数据库，并在同源SOX和POU家族转录因子的DNA结合域的关键结构界面上确定了反复突变的位置。通过将小鼠胚胎成纤维细胞转化为诱导多能干细胞作为功能读数，我们发现了几个增强SOX2和OCT4多能重编程的功能增益突变。野生型SOX17不支持重编程，但反复出现的错义突变SOX17 - V118M能够诱导多能性。此外，SOX17‐V118M促进致癌转化，增强热稳定性并提高SOX17的细胞蛋白水平。我们的结论是，SOX和POU家族因子在癌症中的突变特征可以指导高效重编程因子的设计。此外，我们建议将细胞重编程作为研究癌症相关突变对功能影响的合适方法。
The functional consequences of cancer‐associated missense mutations are unclear for the majority of proteins. We have previously demonstrated that the activity of SOX and Pit‐Oct‐Unc (POU) family factors during pluripotency reprogramming can be switched and enhanced with rationally placed point mutations. Here, we interrogated cancer mutation databases and identified recurrently mutated positions at critical structural interfaces of the DNA‐binding domains of paralogous SOX and POU family transcription factors. Using the conversion of mouse embryonic fibroblasts to induced pluripotent stem cells as functional readout, we identified several gain‐of‐function mutations that enhance pluripotency reprogramming by SOX2 and OCT4. Wild‐type SOX17 cannot support reprogramming but the recurrent missense mutation SOX17‐V118M is capable of inducing pluripotency. Furthermore, SOX17‐V118M promotes oncogenic transformation, enhances thermostability and elevates cellular protein levels of SOX17. We conclude that the mutational profile of SOX and POU family factors in cancer can guide the design of high‐performance reprogramming factors. Furthermore, we propose cellular reprogramming as a suitable assay to study the functional impact of cancer‐associated mutations.