One of the major biological actions of interferons (IFNs) is its antigrowth/antitumor effect; a property that has allowed IFNs to be used clinically in the treatment of a variety of malignancies. The growth inhibitory effects of these cytokines are complex, and the role programmed cell death or """"""""apoptosis"""""""" plays in their antitumor effects is variable and not very well understood. Expression of specific cellular genes induced by either IFNa/b (Type 1) or IFNg (Type 2) is believed to mediate the biological actions of these cytokines. Transcriptional activation of genes triggered by IFNs is mediated primarily by the activation of the Jak/Stat signaling pathway. The Janus family of protein tyrosine kinases (Jak1, Jak2, Jak3 and Tyk2) induces tyrosine phosphorylation and dimerization of specific transcription factors called Stats. These homodimeric or heterodimeric Stat complexes translocate to the nucleus where they bind to enhancers found within IFN regulated genes. In addition to IFN activation of the Jak/ Stat pathway, other signaling pathways can be regulated by IFNs that may contribute to the biological effects of these cytokines. The antigrowth but not the antiviral effects of type 1 IFNs in T cells have been shown to require early signaling components of the T-cell receptor (TCR) signal transduction pathway: Lck, Zap70 and CD45, suggesting that there is cross-talk between these two signaling cascades. Recently, we characterized a TCR signaling deficient human leukemic T cell Jurkat line variant that undergoes apoptosis when stimulated in the presence of IFNa/b, but has a deficiency in mobilizing calcium when activated via the TCR. In contrast, the parental line only exhibits antigrowth responses in the absence of apoptosis after IFN treatment with intact TCR mediated responses. Preliminary results point that the NFAT family of transcription factors, which mediate the expression of cytokine genes, might also play a role in IFNa/b signaling. Therefore, this identifies NFAT as another shared TCR signaling component in the IFN signal transduction pathway. It is still unresolved how NFAT participates in the IFN a/b mediated antiproliferative response and whether these two signaling cascades reciprocally regulate each other. Using these two T-cell lines as our model system and knock-out mice, the information gained from these studies will help understand the mechanism of IFNs actions. First: what molecular events and genes must be induced by IFNs to turn on the """"""""suicide"""""""" signal in tumor cells? Second: what role IFNs play in T cell biology? The fundamental goals of this laboratory are to understand the following: (i) The molecular mechanisms how and why IFNa/b regulates apoptosis in certain tumor cells and only an antiproliferative effect in other tumors. We are interested in identifying and classifying a set of IFN inducible genes that are required for apoptosis or antiproliferation. It is also of great interest to identify the mutation harbored in the Jurkat variant that renders them susceptible to undergo apoptosis in response to type I IFNs. Furthermore, the role components of the Jak/Stat signaling cascade play in the apoptotic process initiated by type I IFNs will be evaluated using Type I IFN Resistant Clones derived from the Jurkat variant line containing mutations in either Stat or Jak family members. (ii) The role the NFAT family of transcription factors plays in type I IFN signaling. Analyze whether the antigrowth response initiated by IFN is regulated by NFAT in T cells. Determine whether one or many NFAT members (i.e. NFAT1, NFAT2, NFAT3, NFAT4) are required for IFN-mediated antiproliferative activities. Identify which subset of T cells (CD4 vs. CD8) is responding to the antigrowth actions of IFNa/b and whether any of these cell populations undergo apoptosis.
|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|