Mutant p53 cooperates with the SWI-SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells.pdf (815.82 kB)
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Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells

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posted on 21.12.2021, 03:31 authored by NT Pfister, V Fomin, K Regunath, JY Zhou, W Zhou, L Silwal-Pandit, WA Freed-Pastor, O Laptenko, SP Neo, J Bargonetti, Paul NeilsenPaul Neilsen
© 2015, Pfister et al. Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines. Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growth in two-dimensional (2D) and three-dimensional (3D) culture conditions. Mutant p53 binds near the VEGFR2 promoter transcriptional start site and plays a role in maintaining an open conformation at that location. Relatedly, mutant p53 interacts with the SWI/SNF complex, which is required for remodeling the VEGFR2 promoter. By both querying individual genes regulated by mutant p53 and performing RNA sequencing, the results indicate that > 40% of all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of theSWI/SNFchromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to antiVEGFtherapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential.

Funding

Other

History

Volume

29

Issue

12

Start Page

1298

End Page

1315

Number of Pages

19

eISSN

1549-5477

ISSN

0890-9369

Publisher

Cold Spring Harbor Laboratory Press

Peer Reviewed

Yes

Open Access

Yes

External Author Affiliations

Columbia University; Oslo University Hospital; Massachusetts General Hospital; Agency for Science, Technology, and Research, Singapore; City University of New York; Rutgers New Jersey Medical School; National University of Singapore; Swinburne University of Technology

Era Eligible

Yes

Journal

Genes and Development