Bacterial cyclomodulin Cif blocks the host cell cycle by stabilizing the cyclin-dependent kinase inhibitors p21 and p27.
The cycle inhibiting factor (Cif) is a cyclomodulin produced by enteropathogenic and enterohemorrhagic Escherichia coli. Upon injection into the host cell by the bacterial type III secretion system, Cif inhibits the G2/M transition via sustained inhibition of the mitosis inducer CDK1 independently of the DNA damage response. In this study, we show that Cif induces not only G2, but also G1 cell cycle arrest depending on the stage of cells in the cell cycle during the infection. In various cell lines including differentiated and untransformed enterocytes, the cell cycle arrests are correlated with the accumulation of the cyclin-dependent kinase inhibitors p21(waf1/cip1) and p27(kip1). Cif-induced cyclin-dependent kinase inhibitor accumulation is independent of the p53 pathway but occurs through inhibition of their proteasome-mediated degradation. Our results provide a direct link between the mode of action of Cif and the host cell cycle control.
Samba-Louaka
Ascel
A
INRA, UMR 1225, F-31076 Toulouse, France.
Nougayrède
Jean-Philippe
JP
Watrin
Claude
C
Jubelin
Grégory
G
Oswald
Eric
E
Taieb
Frédéric
F
D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004926:Escherichia coli / Q000502:physiology*; D029968:Escherichia coli Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*
C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; C481998:Cif protein, E coli; D050759:Cyclin-Dependent Kinase Inhibitor p21; D029968:Escherichia coli Proteins; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016203:CDC2 Protein Kinase