Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis

Yue E. Chin, Motoo Kitagawa, Keisuke Kuida, Richard A. Flavell, Xin Yuan Fu

Research output: Contribution to journalArticle

434 Scopus citations


Protein tyrosine kinases activate the STAT (signal transducer and activator of transcription) signaling pathway, which can play essential roles in cell differentiation, cell cycle control, and development. However, the potential role of the STAT signaling pathway in the induction of apoptosis remains unexplored. Here we show that gamma interferon (IFN-γ) activated STAT1 and induced apoptosis in both A431 and HeLa cells, whereas epidermal growth factor (EGF) activated STAT proteins and induced apoptosis in A431 but not in HeLa cells. EGF receptor autophosphorylation and mitogen-activated protein kinase activation in response to EGF were similar in both cell lines. The breast cancer cell line MDA-MB-468 exhibited a similar response to A431 cells, i.e., STAT activation and apoptosis correlatively resulted from EGF or IFN-γ treatment. In addition, in a mutant A431 cell line in which STAT activation was abolished, no apoptosis was induced by either EGF or IFN-γ. We further demonstrated that both EGF and IFN-γ induced caspase 1 (interleukin-1β converting enzyme [ICE]) gene expression in a STAT-dependent manner. IFN-γ was unable to induce ICE gene expression and apoptosis in either JAK1-deficient HeLa cells (E2A4) or STAT1-deficient cells (U3A). However, ICE gene expression and apoptosis were induced by IFN-γ in U3A cells into which STAT1 had been reintroduced. Moreover, both EGF-induced apoptosis and IFN-γ-induced apoptosis were effectively blocked by Z-Val- Ala-Asp-fluoromethylketone (ZVAD) in all the cells tested, and studies from ICE-deficient cells indicate, I that ICE gene expression was necessary for IFN-γ-induced apoptosis. We conclude that activation of the STAT signaling pathway can induce apoptosis through the induction of ICE gene expression.

Original languageEnglish (US)
Pages (from-to)5328-5337
Number of pages10
JournalMolecular and cellular biology
Issue number9
StatePublished - Sep 1997

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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