Induction of Apoptosis by Protein Inhibitor of Activated Stat1 through c-Jun NH2-terminal Kinase Activation

Bin Liu,Ke Shuai

doi:10.1074/jbc.m101085200

Abstract

Members of the protein inhibitor of activated signal transducer and activator of transcription (STAT) family (PIAS family) of proteins act as negative regulators of STATs in cytokine signaling. We report here that PIAS proteins have proapoptotic activity. PIAS1 induced apoptosis in both human 293T cells and human osteosarcoma U2OS cells. PIAS1 is localized in the nucleus as distinct nuclear dots. Ectopic expression of PIAS1 in U2OS cells activated JNK1 (c-Jun NH(2)-terminal kinase). A dominant-negative JNK1, capable of inhibiting PIAS1-induced JNK1 activation, blocked PIAS1-mediated apoptosis. Furthermore, a mutant PIAS1, lacking the first 9 amino acid residues, failed to repress Stat1-mediated gene activation although it retained its ability to activate JNK and to trigger apoptosis. Our results identify a novel function of PIAS1 in the induction of JNK-dependent apoptosis, independent of the previously known inhibitory activity of PIAS1 in STAT-mediated gene activation.

Highlights

The c-Jun NH2-terminal kinase (JNK)1 is activated by a variety of cellular signals including growth factors, inflammatory cytokines, and environmental stress [1]
When cells were stained with Hoechst dye, an enriched population of cells with condensed nuclei, characteristic of apoptosis, were observed in samples transfected with PIAS1 (Fig. 1A, panel j)
We have provided strong evidence to demonstrate a novel function of PIAS1 in the activation of JNK and apoptosis

Summary

Introduction

The c-Jun NH2-terminal kinase (JNK)1 is activated by a variety of cellular signals including growth factors, inflammatory cytokines, and environmental stress [1]. A mutant PIAS1, lacking the first 9 amino acid residues, failed to repress Stat1-mediated gene activation it retained its ability to activate JNK and to trigger apoptosis. PIASx␣ or PIASx␤ induced apoptosis when overexpressed in 293T cells, their apoptotic activity was weaker as compared with that of PIAS1, PIAS3, or PIASy as indicated by less apoptotic body formation as well as less nuclear condensation.2 These results suggest that the PIAS family of proteins has proapoptotic activity.

Results

Conclusion