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Prolonged STAT1 Activation Related to the Growth Arrest of Malignant
Lymphoma Cells by Interferon-
Philip M. Grimley,
Hui Fang,
Hallgeir Rui,
Emanuel F. Petricoin
III, Subhransu Ray,
Fan Dong,
Karen H. Fields,
Renqiu Hu,
Kathryn C. Zoon,
Susette Audet, and
Judy Beeler
From the Department of Pathology, Uniformed Services University of
the Health Sciences, Bethesda, MD; and the Center for Biologics,
Evaluation and Research, Food and Drug Administration,
Bethesda, MD.
Multiple biologic effects of interferon- (IFN-), including
cell growth inhibition and antiviral protection, are initiated by
tyrosine phosphorylation of STAT proteins. Although this signal pathway
has been intensively investigated, the relevance of STAT signal
persistence has received scant attention. Using paired isogenic
lymphoma cells (Daudi), which either are sensitive or resistant to
growth inhibition by IFN-, we found comparable initial tyrosine
phosphorylation of multiple STAT proteins; however, the phosphorylation
durations and associated DNA-binding activities diverged.
Phosphorylation and DNA-binding capacity of STAT1 decreased after 4 to
8 hours in resistant cells, as compared with 24 to 32 hours in
sensitive cells, whereas phosphorylation of STAT3 and STAT5b was
briefer in both lines. Functional significance of the prolonged STAT1
signal, therefore, was explored by experimental interruption of
tyrosine phosphorylation, either by premature withdrawal of the IFN-
or deferred addition of pharmacologically diverse antagonists:
staurosporine (protein kinase inhibitor), phorbol 12-myristate
13-acetate (growth promoter), or aurintricarboxylic acid (ligand
competitor). Results indicated that an approximately 18-hour period of
continued STAT1 phosphorylation was associated with growth arrest, but
that antiviral protection developed earlier. These differences provide
novel evidence of a temporal dimension to IFN- signal specificity
and show that duration of STAT1 activation may be a critical variable
in malignant cell responsiveness to antiproliferative therapy.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 3017-3027
© 1998 by The American Society of Hematology.
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