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J. Exp. Med.,
Volume 188, Number 2, July 20, 1998 247-254
By
From the Stanford University School of Medicine, Department of Medicine, Division of Immunology
and Rheumatology, Stanford, California 94305-5111
Inducible gene expression is primarily regulated at the level of transcription. Additional steps of
"processing" pre-mRNA, involved in the regulation of induced gene expression, have not been previously reported. Here we report a novel mechanism of "activation-induced splicing"
of preexisting tumor necrosis factor (TNF) message (pre-mRNA) in naive T lymphocytes after
engagement of the T cell receptor (TCR), which still occurs after inhibition of transcription.
Expression of TNF has been previously demonstrated to be regulated at both the transcriptional and translational levels. However, neither the large pool of TNF mRNA observed in activated T cells nor TNF protein production, which peaks very shortly after activation, can be
solely attributed to increased transcription. Evidence is presented that activation-induced splicing of TNF pre-mRNA plays a significant role in the rapid production of TNF seen in activated T cells. Activation triggers processing of TNF pre-mRNA that has accumulated in naive
T cells (before activation-induced transcription), and the mature TNF mRNA is translocated
to the cytoplasm for rapid translation and protein production. This novel form of activation-induced
splicing of TNF may allow T cells to mount an immediate response to activation stimuli under
physiological conditions.
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