The winged helix (WH) proteins form a growing family of transcriptional regulators that share a conserved DNA binding domain. These proteins function as developmental switches. They determine tissue and organ differentiation in vertebrate and invertebrate animals. WH proteins have oncogenic potential; gain of function mutations in these proteins act in a dominant fashion to cause cancer in animals (avian sarcomas) and humans (alveolar rhabdomyosarcoma and acute lymphoblastic leukemia). The goal of the proposed research is an understanding of the molecular mechanisms that operate in WH oncogenesis. The proteins to be studied are Qin, a telencephalon-specific protein that is also expressed as the oncogenic determinant in a retrovirus, CWH2, a mutant form of the chicken homolog of mesenchyme forkhead protein, and the human fusion proteins PAX3-FKHR and PAX7-FKHR, the putative causes of alveolar rhabdomyosarcoma. Mutations that activate the oncogenic potential of WH proteins will be defined, and their effects on DNA binding and transcriptional regulation will be determined. Interactions between WH proteins and the transcription preinitiation complex will be studied, and the participation of coregulators in this interaction will be tested. Finally, downstream targets of WH proteins will be identified and isolated, and their roles in the transformation process will be determined. Aberrant transcriptional regulation lies at the heart of oncogenesis. The nature of activating mutations, the interactions with the preinitiation complex, and the identity and function of target genes will reveal novel molecular targets for therapeutic intervention.
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