期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 281, 期 34, 页码 24182-24192出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M601871200
关键词
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资金
- NCI NIH HHS [CA 98454, CA 51085] Funding Source: Medline
Tumor necrosis factor alpha( TNF alpha) is a potent pleiotropic cytokine produced by many cells in response to inflammatory stress. The molecular mechanisms responsible for the multiple biological activities of TNF alpha are due to its ability to activate multiple signal transduction pathways, including nuclear factor kappa B ( NF kappa B), which plays critical roles in cell proliferation and survival. TNF alpha displays both apoptotic and antiapoptotic properties, depending on the nature of the stimulus and the activation status of certain signaling pathways. Here we show that TNF alpha can lead to the induction of NF kappa B signaling with a concomitant increase in spermidine/spermine N-1-acetyltransferase ( SSAT) expression in A549 and H157 non-small cell lung cancer cells. Induction of SSAT, a stress-inducible gene that encodes a rate-limiting polyamine catabolic enzyme, leads to lower intracellular polyamine contents and has been associated with decreased cell growth and increased apoptosis. Stable overexpression of a mutant, dominant negative I kappa B alpha protein led to the suppression of SSAT induction by TNF alpha in these cells, thereby substantiating a role of NF kappa B in the induction of SSAT by TNF alpha. SSAT promoter deletion constructs led to the identification of three potential NF kappa B response elements in the SSAT gene. Electromobility shift assays, chromatin immunoprecipitation experiments and mutational studies confirmed that two of the three NF kappa B response elements play an important role in the regulation of SSAT in response to TNF alpha. The results of these studies indicate that a common mediator of inflammation can lead to the induction of SSAT expression by activating the NF kappa B signaling pathway in non-small cell lung cancer cells.
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