| Vertebrate Tob/BTG proteins possess antiproliferative activity and can be tumor-suppressors. The C. elegans genome encodes a single protein, FOG-3, with amino acid sequence similarity to Tob/BTG proteins. FOG-3 was originally identified as a terminal regulator of sperm fate specification. My thesis focuses on the role of FOG-3 in cell proliferation. Most importantly, I found that FOG-3 has both antiproliferative and tumor-suppressor activities, establishing a critical functional link between nematode FOG-3 and its vertebrate orthologs. In addition, FOG-3 can promote germline proliferation and serve as an oncogene. These opposite effects on proliferation are context-dependent and dose-sensitive. I propose a model suggesting that low FOG-3 promotes proliferation while high FOG-3 blocks proliferation. This idea opens the possibility that Tob/BTG proteins may have a broader role in proliferation control than previously thought.;My thesis also explores other aspects of fog-3 biology. Using genetic epistasis experiments, I placed fog-3 in the genetic pathway of germline proliferation control. My results suggest that FOG-3 acts downstream of GLP-1/Notch signaling and upstream of the GLD proteins. Using genetic mosaics, I found that fog-3 functions in germ cells to promote the sperm fate. I also found that FOG-3 localizes in the cytoplasm to sites of RNA regulation and that FOG-3 abundance is regulated by the FBF RNA-binding protein. Finally, I sought FOG-3-associated factors, both by yeast two-hybrid screening and by co-immunoprecipitation experiments, and obtained preliminary evidence that FOG-3 associates with RNA regulators. |
