The tumor suppressor Rb is a phosphoprotein that blocks cell cycle progression by modulating the functions of E2F-containing transcription factors. The importance of Rb for protecting the cell from inappropriate cell division is demonstrated by the almost universal inactivation of the Rb pathway in carcinomas. Since this pathway is defective in almost all carcinomas, one approach to specifically attack cancer cells is to inactivate proteins essential for the survival of cells with Rb pathway defects but not essential for those with an intact Rb pathway. The nematode Caenorhabditis elegans has a single Rb family member, lin-35 Rb, which can be inactivated with relatively minor effects on the growth of the animal. lin-35 Rb has been shown to interact genetically with the worm homologs of many mammalian Rb-interacting proteins and therefore can serve as a model to study Rb function in vivo. I am using C. elegans to search for genes that are synthetically lethal with Rb to identify new molecular pathways parallel to the Rb pathway which could define new cancer-related pathways. To do so, I am using an RNA interference (RNAi) library. Because Iin-35 Rb animals are less healthy than wild-type animals, it is possible that some of the synthetic phenotypes seen in lin-35 Rb mutants but not in wild-type animals are caused by the non-specific additive effects of two harmful mutations. To address the issue of cell-autonomous synthetic lethality (i.e., whether the synthetic effects of two mutations occur within a single cell), I am developing tissue-specific assays for synthetic lethality. All genes whose inactivation by RNAi results in a different phenotype in lin-35 Rb worms from that in wild-type worms will be tested in a tissue-specific assay. For candidates that appear to be cell-autonomously synthetically lethal and that have mammalian homologs, mammalian cells either containing or lacking Rb will be treated with RNAi to the mammalian homologs to assess whether the synthetic lethality seen in worms also occurs in mammals. Gene products whose inactivation is synthetically lethal with inactivated lin-35 Rb may be therapeutic targets in mammals since their inactivation may specifically kill tumor cells (in which the Rb pathway is almost always inactivated) and leave cells containing functional Rb unharmed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA104890-04
Application #
7245150
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lohrey, Nancy
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$136,080
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Anderson, Courtney; Zhou, Shan; Sawin, Emma et al. (2012) SLI-1 Cbl inhibits the engulfment of apoptotic cells in C. elegans through a ligase-independent function. PLoS Genet 8:e1003115
Vanderzalm, Pamela J; Pandey, Amita; Hurwitz, Michael E et al. (2009) C. elegans CARMIL negatively regulates UNC-73/Trio function during neuronal development. Development 136:1201-10
Hurwitz, Michael E; Vanderzalm, Pamela J; Bloom, Laird et al. (2009) Abl kinase inhibits the engulfment of apoptotic [corrected] cells in Caenorhabditis elegans. PLoS Biol 7:e99