One of the major biological actions of type I interferons (IFNs) is the antigrowth and antitumor effects they exert on tumor cells, a major property that captured the attention of many in the cancer field and allowed the clinical application of IFNs for the treatment of a variety of cancers. The mechanisms of growth inhibition of IFNs are complex as these cytokines can elicit their antigrowth actions by promoting cell cycle arrest or by triggering programmed cell death or """"""""apoptosis"""""""". This latter cell death mechanism remains poorly understood. Our work has identified the signal transducer and activator of transcription (STAT)2 as a critical mediator in the promotion of type I interferon-induced apoptosis. In our cell line model, loss of STAT2 prevents the activation of the mitochondrial death pathway triggered by type I IFNs. Most importantly, we have identified a novel motif in STAT2 that controls IFN-induced apoptosis. These findings have prompted us to examine carefully a number of STAT2 single nucleotide polymorphisms (SNPs) recently identified in the human population as these mutations might have the capacity to alter STAT2 transcriptional function and consequently type I IFN biological responses. Thus far we have characterized one of these STAT2 SNPs, which enhance the antiproliferative effects of type I IFNs. Collectively our findings strongly suggest that STAT2 is a critical component in the activation of apoptosis induced by type I IFNs and specific STAT2 mutations may be counterproductive or beneficial to the host.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
United States
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Maher, Stephen G; Sheikh, Faruk; Scarzello, Anthony J et al. (2008) IFN-alpha and IFN-lambda differ in their antiproliferative effects and duration of JAK/STAT signaling activity. Cancer Biol Ther 7:nihpa47781
Scarzello, Anthony J; Romero-Weaver, Ana L; Maher, Stephen G et al. (2007) A Mutation in the SH2 domain of STAT2 prolongs tyrosine phosphorylation of STAT1 and promotes type I IFN-induced apoptosis. Mol Biol Cell 18:2455-62
Gamero, Ana M; Potla, Ramesh; Sakamoto, Shuji et al. (2006) Type I interferons activate apoptosis in a Jurkat cell variant by caspase-dependent and independent mechanisms. Cell Signal 18:1299-308