Sustained oscillations of NF-κB produce distinct genome scanning and gene expression profiles

Myong Hee Sung, Luigi Salvatore, Rossana De Lorenzi, Anindya Indrawan, Manolis Pasparakis, Gordon L. Hager, Marco E. Bianchi, Alessandra Agresti

Research output: Contribution to journalArticle

Abstract

NF-κB is a prototypic stress-responsive transcription factor that acts within a complex regulatory network. The signaling dynamics of endogenous NF-κB in single cells remain poorly understood. To examine real time dynamics in living cells, we monitored NF-κB activities at multiple timescales using GFP-p65 knock-in mouse embryonic fibroblasts. Oscillations in NF-κB were sustained in most cells, with several cycles of transient nuclear translocation after TNF-α stimulation. Mathematical modeling suggests that NF-κB oscillations are selected over other non-oscillatory dynamics by fine-tuning the relative strengths of feedback loops like IκB2a. The ability of NF-κB to scan and interact wit1h the genome in vivo remained remarkably constant from early to late cycles, as observed by fluorescence recovery after photobleaching (FRAP). Perturbation of long-term NF-κB oscillations interfered with its short-term interaction with chromatin and balanced transcriptional output, as predicted by the mathematical model. We propose that negative feedback loops do not simply terminate signaling, but rather promote oscillations of NF-κB in the nucleus, and these oscillations are functionally advantageous.

Original languageEnglish
Article numbere7163
JournalPLoS One
Volume4
Issue number9
DOIs
Publication statusPublished - Sep 29 2009

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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