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Article: Cancer‐associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17

TitleCancer‐associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17
Authors
Keywordscancer mutations
gain‐of‐function mutations
induced pluripotency
SOX17
variants of uncertain significance
Issue Date2020
PublisherWiley-Blackwell Publishing Ltd.. The Journal's web site is located at http://www.febsjournal.org/
Citation
The FEBS Journal, 2020, v. 287 n. 1, p. 122-144 How to Cite?
AbstractThe 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.
Persistent Identifierhttp://hdl.handle.net/10722/280344
ISSN
2019 Impact Factor: 4.392
2015 SCImago Journal Rankings: 2.141

 

DC FieldValueLanguage
dc.contributor.authorSrivastava, Y-
dc.contributor.authorTAN, DS-
dc.contributor.authorMalik, V-
dc.contributor.authorWENG, M-
dc.contributor.authorJaved, A-
dc.contributor.authorCojocaru, V-
dc.contributor.authorWu, G-
dc.contributor.authorVeerapandian, V-
dc.contributor.authorCheung, LWT-
dc.contributor.authorJauch, R-
dc.date.accessioned2020-02-07T07:39:47Z-
dc.date.available2020-02-07T07:39:47Z-
dc.date.issued2020-
dc.identifier.citationThe FEBS Journal, 2020, v. 287 n. 1, p. 122-144-
dc.identifier.issn1742-464X-
dc.identifier.urihttp://hdl.handle.net/10722/280344-
dc.description.abstractThe 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.-
dc.languageeng-
dc.publisherWiley-Blackwell Publishing Ltd.. The Journal's web site is located at http://www.febsjournal.org/-
dc.relation.ispartofThe FEBS Journal-
dc.rightsPreprint This is the pre-peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Postprint This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.-
dc.subjectcancer mutations-
dc.subjectgain‐of‐function mutations-
dc.subjectinduced pluripotency-
dc.subjectSOX17-
dc.subjectvariants of uncertain significance-
dc.titleCancer‐associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17-
dc.typeArticle-
dc.identifier.emailJaved, A: javed@hku.hk-
dc.identifier.emailCheung, LWT: lydiacwt@hku.hk-
dc.identifier.emailJauch, R: ralf@hku.hk-
dc.identifier.authorityJaved, A=rp02386-
dc.identifier.authorityCheung, LWT=rp02137-
dc.identifier.authorityJauch, R=rp02383-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1111/febs.15076-
dc.identifier.pmid31569299-
dc.identifier.scopuseid_2-s2.0-85074420973-
dc.identifier.hkuros309121-
dc.identifier.volume287-
dc.identifier.issue1-
dc.identifier.spage122-
dc.identifier.epage144-
dc.publisher.placeUnited Kingdom-

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