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The mutant p53-ID4 complex controls VEGFA isoforms by recruiting lncRNA MALAT1

Pruszko, Magdalena; Milano, Elisa; Forcato, Mattia; Donzelli, S.; Ganci, Federica; Di Agostino, Silvia; De Panfilis, Simone; Fazi, Francesco; Bates, David O.; Bicciato, Silvio; Zylicz, Maciej; Żylicz, Alicja; Blandino, Giovanni; Fontemaggi, Giulia

Authors

Magdalena Pruszko

Elisa Milano

Mattia Forcato

S. Donzelli

Federica Ganci

Silvia Di Agostino

Simone De Panfilis

Francesco Fazi

David O. Bates

Silvio Bicciato

Maciej Zylicz

Alicja Żylicz

Giovanni Blandino

Giulia Fontemaggi



Abstract

The abundant, nuclear-retained, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been associated with a poorly differentiated and aggressive phenotype of mammary carcinomas. This long non-coding RNA (lncRNA) localizes to nuclear speckles, where it interacts with a subset of splicing factors and modulates their activity. In this study, we demonstrate that oncogenic splicing factor SRSF1 bridges MALAT1 to mutant p53 and ID4 proteins in breast cancer cells. Mutant p53 and ID4 delocalize MALAT1 from nuclear speckles and favor its association with chromatin. This enables aberrant recruitment of MALAT1 on VEGFA pre-mRNA and modulation of VEGFA isoforms expression. Interestingly, VEGFA-dependent expression signatures associate with ID4 expression specifically in basal-like breast cancers carrying TP53 mutations. Our results highlight the key role for MALAT1 in control of VEGFA isoforms expression in breast cancer cells expressing gain-of-function mutant p53 and ID4 proteins.

Journal Article Type Article
Journal EMBO Reports
Print ISSN 1469-221X
Electronic ISSN 1469-3178
Publisher EMBO Press
Peer Reviewed Peer Reviewed
Article Number e201643370
APA6 Citation Pruszko, M., Milano, E., Forcato, M., Donzelli, S., Ganci, F., Di Agostino, S., …Fontemaggi, G. (in press). The mutant p53-ID4 complex controls VEGFA isoforms by recruiting lncRNA MALAT1. EMBO Reports, doi:10.15252/embr.201643370
DOI https://doi.org/10.15252/embr.201643370
Keywords lncRNA, MALAT1, ASF/SF2, SRSF1, ID4, mutant p53, VEGFAxxxb, VEGFA
Publisher URL http://embor.embopress.org/content/early/2017/06/26/embr.201643370
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf


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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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