CYTOKINE INDUCIBLE GENES IN HEMATOPOIESIS

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DESCRIPTION: (Adapted from investigator's abstract) The cDNA encoding CIGTA1 (Cytokine lnducible Gene with Transcription Activation and Transformation Activities) was isolated in the P.I.'s laboratory by differential display using mRNAs from a murine T cell line, D10, following stimulation with cytokines within the IL-2 receptor (IL-2R) gamma chain superfamily. The induced expression of CIGTA1 by IL-2R gamma chain cytokines appears to be mediated, at least in part, through the JAK/Stat signaling pathway. CIGTA1 is a nuclear protein with transcriptional activation function and may represent a founding member of a new family of transcription factors. Interestingly, overexpression of CIGTA1 resulted in the conversion of factor-dependent cells to cytokine-independent growth, the loss of contact inhibition and the anchorage-independent growth of fibroblasts in soft agar, demonstrating the oncogenic potential of this molecule. One of the PI's long term research interests has been to understand the process of how cytokine signaling correlates with biological functions and the mechanisms of cytokine dysregulation in human diseases. The cloning of a primary response gene with transactivation and transformation functions allows the PI's group to test the following hypotheses: (1) CIGTA1 can activate many downstream target genes, interact with different protein molecules and in turn, be involved in different biological processes; (2) Different functional domains may be involved in transactivation, transformation, protein-protein interactions and biological functions mediated by different biological stimuli; and (3) Expression of CIGTA1 can be induced by different biological stimuli and the expression is mediated by Stat and other transcription factors. To test these hypotheses, it is proposed to (1) identify cellular target genes for CIGTA1 and ClGTA1-associated proteins; (2) determine the domains of CIGTA1 responsible for its multiple functions; (3) determine whether CIGTA1 expression can be stimulated by other biological stimuli and whether its expression correlates with cell differentiation or cell cycle progression; and (4) determine whether Stat binding site and Stat are the only cis DNA element and transacting factor responsible for CIGTA1 expression. The elucidation of the CIGTA1 gene, its gene product, its cellular target sequences and its interacting proteins is essential for a full understanding of the role of CIGTA1 in different biological processes and various disease states, including cancer.