Plk1 Regulates the Repressor Function of FoxM1b by inhibiting its Interaction with the Retinoblastoma Protein

Nishit K. Mukhopadhyay, Vaibhav Chand, Akshay Pandey, Dragana Kopanja, Janai R. Carr, Yi Ju Chen, Xiubei Liao, Pradip Raychaudhuri

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

FoxM1b is a cell cycle-regulated transcription factor, whose over-expression is a marker for poor outcome in cancers. Its transcriptional activation function requires phosphorylation by Cdk1 or Cdk2 that primes FoxM1b for phosphorylation by Plk1, which triggers association with the co-activator CBP. FoxM1b also possesses transcriptional repression function. It represses the mammary differentiation gene GATA3 involving DNMT3b and Rb. We investigated what determines the two distinct functions of FoxM1b: activation and repression. We show that Rb binds to the C-terminal activation domain of FoxM1b. Analyses with phospho-defective and phospho-mimetic mutants of FoxM1b identified a critical role of the Plk1 phosphorylation sites in regulating the binding of FoxM1b to Rb and DNMT3b. That is opposite of what was seen for the interaction of FoxM1b with CBP. We show that, in addition to GATA3, FoxM1b also represses the mammary luminal differentiation marker FoxA1 by promoter-methylation, and that is regulated by the Plk1 phosphorylation sites in FoxM1b. Our results show that the Plk1 phosphorylation sites in FoxM1b serve as a regulator for its repressor function, and they provide insights into how FoxM1b inhibits differentiation genes and activates proliferation genes during cancer progression.

Original languageEnglish (US)
Article number46017
JournalScientific reports
Volume7
DOIs
StatePublished - Apr 7 2017

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Plk1 Regulates the Repressor Function of FoxM1b by inhibiting its Interaction with the Retinoblastoma Protein'. Together they form a unique fingerprint.

  • Cite this

    Mukhopadhyay, N. K., Chand, V., Pandey, A., Kopanja, D., Carr, J. R., Chen, Y. J., Liao, X., & Raychaudhuri, P. (2017). Plk1 Regulates the Repressor Function of FoxM1b by inhibiting its Interaction with the Retinoblastoma Protein. Scientific reports, 7, [46017]. https://doi.org/10.1038/srep46017