C. elegans FOG-3/Tob can either promote or inhibit germline proliferation, depending on gene dosage and genetic context

• Published in: Oncogene Vol. 32; no. 21; pp. 2614 - 2621
• Main Authors: Snow, J J, Lee, M-H, Verheyden, J, Kroll-Conner, P L, Kimble, J
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 23.05.2013
• Subjects: Alleles; Analysis; Animals; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cancer; Cell culture; Cell differentiation; Cell Proliferation; Cellular biology; Dosage; Gene dosage; Gene Dosage - genetics; Gene Dosage - physiology; Gene expression; Genetic aspects; Germ cells; Germ Cells - cytology; Germ Cells - metabolism; Heterozygotes; Mice; Mutants; Mutation; Neoplasms - genetics; Neoplasms - metabolism; Phenotypes; Physiological aspects; Proteins; RNA-binding protein; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Tissue culture; Translocation (Genetics); Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumorigenesis; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.291

Vertebrate Tob/BTG proteins inhibit cell proliferation when overexpressed in tissue-culture cells, and they can function as tumor suppressors in mice. The single Caenorhabditis elegans Tob/BTG ortholog, FOG-3, by contrast, was identified from its loss-of-function phenotype as a regulator of sperm fate specification. Here we report that FOG-3 also regulates proliferation in the germline tissue. We first demonstrate that FOG-3 is a positive regulator of germline proliferation. Thus, fog-3 null mutants possess fewer germ cells than normal, a modest but reproducible decrease observed for each of two distinct fog-3 null alleles. A similar decrease also occurred in fog-3/+ heterozygotes, again for both fog-3 alleles, revealing a haplo-insufficient effect on proliferation. Therefore, FOG-3 normally promotes proliferation, and two copies of the fog-3 gene are required for this function. We next overexpressed FOG-3 by removal of FBF, the collective term for FBF-1 and FBF-2, two nearly identical PUF RNA-binding proteins. We find that overexpressed FOG-3 blocks proliferation in fbf-1 fbf-2 mutants; whereas germ cells stop dividing and instead differentiate in fbf-1 fbf-2 double mutants, they continue to proliferate in fog-3; fbf-1 fbf-2 triple mutants. Therefore, like its vertebrate Tob/BTG cousins, overexpressed FOG-3 is 'antiproliferative'. Indeed, some fog-3; fbf-1 fbf-2 mutants possess small tumors, suggesting that FOG-3 can act as a tumor suppressor. Finally, we show that FOG-3 and FBF work together to promote tumor formation in animals carrying oncogenic Notch mutations. A similar effect was not observed when germline tumors were induced by manipulation of other regulators; therefore, this FOG-3 tumor-promoting effect is context dependent. We conclude that FOG-3 can either promote or inhibit proliferation in a manner that is sensitive to both genetic context and gene dosage. The discovery of these FOG-3 effects on proliferation has implications for our understanding of vertebrate Tob/BTG proteins and their influence on normal development and tumorigenesis.