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

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.

Opposing Roles of the Forkhead Box Factors FoxM1 and FoxA2 in Liver Cancer

“…There was no significant difference in FoxA2 expression in the G 2 -M phases (Fig. 5F) because FoxM1 is phosphorylated by Plk1, which blocks binding to Rb (25). We repeated this experiment with 3 independent clones of FoxM1-shRNA cells and observed similar results.…”

Epigenetic deregulation of GATA3 in neuroblastoma is associated with increased GATA3 protein expression and with poor outcomes

“…Others have reported DNA methylation at the GATA3 CGI in breast cancer 43,44 bladder cancer 45 and some leukaemias 46 , with direct evidence that DNA methylation regulates GATA3 expression 46,47 . In our results, GATA3 methylation was confined to the start of the GATA3 antisense transcript (Fig.…”

FOXM1 and Cancer: Faulty Cellular Signaling Derails Homeostasis

“…By transferring phosphate group from ATP to substrates, PLK1 control various G2/M associated cellular processes, namely centrosome maturation, checkpoint recovery, spindle assembly, cytokinesis, and apoptosis. Also, PLK1 phosphorylation sites in FOXM1B serves as a regulator for its repressor function in G1 phase and activator function in S and G2/M phase ( 127 ). FOXM1 has two potential PBD-binding sites (T596 and S678) at its C terminal region and phosphorylate S715 and S724 present within the TAD region of FOXM1 ( 128 ).…”