A common cause of neoplastic transformation and subsequent tumor formation/progression involves deregulation of gene expression via alteration of transcription factor function. The SNAG repression domain, named for its presence in the snail/GFI-1 class of zinc finger transcription factors, is present in a variety of proto-oncogenic transcription factors and developmental regulators. T h e p rototype SNAG domain-containing oncogene, GFI-1 (growth-factor i ndependence-1) is responsible for development of T-cell thymomas. Significantly, these oncogenic functions require a functional SNAG repression domain. However, the molecular mechanisms of SNAG-mediated transcriptional repression, which is responsible for these biological functions are completely unknown. The major goal of this proposal is to completely characterize and define the mechanism of the novel SNAG domain in transcriptional regulation, cell growth and tumorigenesis. In the preliminary data to support this proposal, we have presented evidence for a specific interaction between SNAG repression domain and the LIM domains of Ajuba, which can function as a novel SNAG corepressor. Ajuba shuttles between the cytoplasm and nucleus and may form a novel intracellular signaling system. Ajuba interacts with SNAG in v i vo, co-localizes with it and enhances SNAG-mediated transcriptional repression. We postulate that, in this molecular interaction, Ajuba may function as a scaffold for the assembly of a macromolecular repression complex at the target promoters while the SNAG domain may serve as a nuclear targeting motif in the transport of Ajuba into the nucleus.
The specific aims of this proposal will: 1) provide a high resolution definition of the SNAG-Ajuba molecular interaction; 2) biochemically identify the endogenous SNAG-Ajuba complexes; and 3) define the biological significance of SNAG-Ajuba mediated repression. The information derived from the proposed research will significantly advance our understanding of the role of SNAG zinc-finger transcription factors in transcriptional control of cell growth, and the role of these processes in neoplastic transformations as well as a knowledge about possible therapeutic interventions.
