期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 43, 页码 37741-37757出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.280925
关键词
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资金
- National Institutes of Health (NIH) [AI062885]
- NIH, NHLBI [BAA-HL-02-04]
- NIH [RO1 GM086885]
- University of Texas-Sandia National Laboratories
- Sandia Laboratory
- United States Department of Energy Office of Science through Office of Advanced Scientific Computing Research [07-012783]
- Sandia Corp. [DE-AC04-94AL85000]
The canonical nuclear factor-kappa B (NF-kappa B) signaling pathway controls a gene network important in the cellular inflammatory response. Upon activation, NF-kappa B/RelA is released from cytoplasmic inhibitors, from where it translocates into the nucleus, subsequently activating negative feedback loops producing either monophasic or damped oscillatory nucleo-cytoplasmic dynamics. Although the population behavior of the NF-kappa B pathway has been extensively modeled, the sources of cell-to-cell variability are not well understood. We describe an integrated experimental-computational analysis of NF-kappa B/RelA translocation in a validated cell model exhibiting monophasic dynamics. Quantitative measures of cellular geometry and total cytoplasmic concentration and translocated RelA amounts were used as priors in Bayesian inference to estimate biophysically realistic parameter values based on dynamic live cell imaging studies of enhanced GFP-tagged RelA in stable transfectants. Bayesian inference was performed on multiple cells simultaneously, assuming identical reaction rate parameters, whereas cellular geometry and initial and total NF-kappa B concentration-related parameters were cell-specific. A subpopulation of cells exhibiting distinct kinetic profiles was identified that corresponded to differences in the I kappa B alpha translation rate. We conclude that cellular geometry, initial and total NF-kappa B concentration, I kappa B alpha translation, and I kappa B alpha degradation rates account for distinct cell-to-cell differences in canonical NF-kappa B translocation dynamics.
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