title: Prolonged STAT1 activation related to the growth arrest of malignant lymphoma cells by interferon-alpha.
abstract: Multiple biologic effects of interferon-alpha (IFN-alpha), 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-alpha, 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-alpha 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-alpha signal specificity and show that duration of STAT1 activation may be a critical variable in malignant cell responsiveness to antiproliferative therapy.
authors.affiliation: Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Grimley
authors.forename: H
authors.initials: H
authors.lastname: Fang
authors.forename: H
authors.initials: H
authors.lastname: Rui
authors.forename: E F
authors.initials: EF
authors.lastname: Petricoin
authors.forename: S
authors.initials: S
authors.lastname: Ray
authors.forename: F
authors.initials: F
authors.lastname: Dong
authors.forename: K H
authors.initials: KH
authors.lastname: Fields
authors.forename: R
authors.initials: R
authors.lastname: Hu
authors.forename: K C
authors.initials: KC
authors.lastname: Zoon
authors.forename: S
authors.initials: S
authors.lastname: Audet
authors.forename: J
authors.initials: J
authors.lastname: Beeler
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology*; D008894:Milk Proteins; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D015534:Trans-Activators; D007371:Interferon-gamma