Nearly all of us have been affected by cancer, a deadly disease that has its roots in mitotic dysregulation. Proto-oncogenes, or regulated growth genes, are present in all eukaryotic cells. In many tumors, the regulatory elements that allow for homeostatic growth have been silenced or lost to mutations, resulting in pathological overgrowth of cells. Tetrahymena thermophila are free-living eukaryotic unicellular organisms that generally reproduce asexually via mitosis. Our previous studies have shown that these organisms appear to express homologues of the proto-oncogene, Ras, and its signaling partner, Raf. The Ras/Raf uncoupler BAY-293 reduces mitotic signaling in this organism, apparently by decreasing gene expression as indicated by the increased level of histone acetylation seen with drug treatment.
Another proto-oncogene involved in vertebrate mitotic signaling is the tyrosine phosphatase SHP2, encoded by the gene PTPN11. This protein is instrumental in recruiting a number of pathways involved in mitosis and differentiation, including the Ras/Raf pathway. BLAST searches of the Tetrahymena Genome Database using the SHP2 sequence indicate a high likelihood that Tetrahymena have a SHP2 homolog, making this an intriguing target for drug study. We hypothesized that inhibiting SHP2 would reduce mitosis in Tetrahymena; however, the SHP2 inhibitor PHPS significantly increased cell division in this organism while decreasing histone acetylation. PHPS increased levels of tyrosine phosphorylation and nucleolar activity in Tetrahymena; the distribution of phosphorylation throughout the cell was also affected. In summary, we see that while the Ras homolog in Tetrahymena affects mitosis in a manner that is similar to vertebrates, the SHP2 homolog does not. Therefore, Tetrahymena would be a useful model system in which to study drugs that affect the Ras/Raf portion of growth factor signaling
