Sustained NF-kappaB activation produces a short-term cell proliferation block in conjunction with repressing effectors of cell cycle progression controlled by E2F or FoxM1.
NF-kappaB transcription factors induce a host of genes involved in pro-inflammatory/stress-like responses; but the collateral effects and consequences of sustained NF-kappaB activation on other cellular gene expression programming remain less well understood. Here enforced expression of a constitutively active IKKbeta T-loop mutant (IKKbetaca) drove murine fibroblasts into transient growth arrest that subsided within 2-3 weeks of continuous culture. Proliferation arrest was associated with a G1/S phase block in immortalized and primary early passage MEFs. Molecular analysis in immortalized MEFs revealed that inhibition of cell proliferation in the initial 1-2 weeks after their IKKbetaca retroviral infection was linked to the transient, concerted repression of essential cell cycle effectors that are known targets of either E2F or FoxM1. Co-expression of a phosphorylation resistant IkappaBalpha super repressor and IKKbetaca abrogated growth arrest and cell cycle effector repression, thereby linking IKKbetaca's effects to canonical NF-kappaB activation. Transient growth arrest of IKKbetaca cells was associated with enhanced p21 (cyclin-dependent kinase inhibitor 1A) protein expression, due in part to transcriptional activation by NF-kappaB and also likely due to strong repression of Skp2 and Csk1, both of which are FoxM1 direct targets mediating proteasomal dependent p21 turnover. Ablation of p21 in immortalized MEFs reduced their IKKbetaca mediated growth suppression. Moreover, trichostatin A inhibition of HDACs alleviated the repression of E2F and FoxM1 targets induced by IKKbetaca, suggesting chromatin mediated gene silencing in IKKbetaca's short term repressive effects on E2F and FoxM1 target gene expression.
Penzo
Marianna
M
Centro Ricerca Biomedica Applicata (CRBA), S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy.
Massa
Paul E
PE
Olivotto
Eleonora
E
Bianchi
Francesca
F
Borzi
Rosa Maria
RM
Hanidu
Adedayo
A
Li
Xiang
X
Li
Jun
J
Marcu
Kenneth B
KB
D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D050684:E2F Transcription Factors / Q000378:metabolism*; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000378:metabolism; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction
D050759:Cyclin-Dependent Kinase Inhibitor p21; D017931:DNA Primers; D050684:E2F Transcription Factors; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D012097:Repressor Proteins; D000072000:NF-KappaB Inhibitor alpha; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D006655:Histone Deacetylases