Prolonged STAT1 activation related to the growth arrest of malignant lymphoma cells by interferon-alpha. Blood 1998 Apr 15;91(8):3017-27
Date
05/16/1998Pubmed ID
9531615Scopus ID
2-s2.0-0032523158 (requires institutional sign-in at Scopus site) 36 CitationsAbstract
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.
Author List
Grimley PM, Fang H, Rui H, Petricoin EF 3rd, Ray S, Dong F, Fields KH, Hu R, Zoon KC, Audet S, Beeler JMESH terms used to index this publication - Major topics in bold
Antineoplastic AgentsAntiviral Agents
Cell Division
DNA-Binding Proteins
Gene Expression Regulation, Neoplastic
Humans
Interferon-gamma
Lymphoma
Milk Proteins
Recombinant Proteins
STAT1 Transcription Factor
STAT5 Transcription Factor
Signal Transduction
Trans-Activators
Tumor Cells, Cultured