STAT-1: a novel regulator of apoptosis

Abstract

Extracellular signalling molecules binding to their specific receptors are able to modulate gene expression, leading to changes in development, cell growth and homeostasis. The signal transducers and activators of transcription (STAT) protein family members are among the best studied of the latent cytoplasmic signal-dependent transcription factors. The STAT factors are activated via phosphorylation on the C-terminal domain following cytokine signalling or by various stress-induced stimuli. Recently, STAT-1 has been implicated in modulating pro- and anti-apoptotic genes following several stress-induced responses. These effects are dependent on STAT-1 phosphorylation on serine-727 and require the C-terminal transactivation domain of STAT-1 to enhance its pro-apoptotic effect or inhibit its anti-apoptotic effects. The STAT-1 C-terminal domain has been demonstrated to be important for protein-protein interaction with other transcriptional activators. The reports that STAT-1-deficient mice develop spontaneous and chemically induced tumours more rapidly compared to wild-type mice and that STAT-1-deficient cells are more resistant to agents that induce apoptosis strongly support the argument that STAT-1 acts as a tumour suppressor.

Figure 1

Signal transducers and activators of transcription-1 (STAT-1) activation induced by ischaemia–reperfusion or genotoxic stress acts at several levels to induce apoptosis. (a) STAT-1 can directly activate apoptotic genes. (b) STAT-1 can interact with p53 and induce apoptosis via enhancing the expression of p53-responsive genes. (c) STAT-1 is able to inhibit the activity of the MDM2 gene and, therefore, enhance p53 stability.