The purpose of the current work is to understand the regulation of parafibromin, its physiologic targets, and the mechanism(s) by which its loss of function can lead to neoplastic transformation. To this end we are first trying to identify and characterize the functions parafibromin that are evolutionarily conserved between insects and mammals. Human parafibromin interacts with RNA polymerase II via a human PAF1 complex, whose other protein components include human Paf1, CTR9, Leo1, and the WD40-repeat protein Ski8. The components of the PAF1 complex are highly evolutionarily conserved in Drosophila and parafibromin shares 57% amino acid identity and 71% similarity with Hyrax (Hyx), its ortholog in the fly. Such a high degree of homology suggests a possible conserved functional role of the protein across species. Current work in our laboratory examines such shared functions using Drosophila melanogaster and cultured cells, such as human Hela and HEK-293 cells, as model systems. One line of research uses an insect model system in which Drosophila Hyx (parafibromin) is expressed from a hypomorphic allele. In this model system both hetero- and homozygotes have phenotypes. The other line of research studies the effect of mammalian parafibromin overexpression, mutation or knockdown (by RNA interference) on cell proliferation, cell survival, and expression of other genes important in cell growth and proliferation. White blood cells from patients heterozygous for CDC73/HRPT2 are also studied in vitro.

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2013
Total Cost
$557,791
Indirect Cost
City
State
Country
Zip Code
Lin, Ling; Zhang, Jian-Hua; Panicker, Leelamma M et al. (2008) The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene. Proc Natl Acad Sci U S A 105:17420-5
Agarwal, Sunita K; Simonds, William F; Marx, Stephen J (2008) The parafibromin tumor suppressor protein interacts with actin-binding proteins actinin-2 and actinin-3. Mol Cancer 7:65