Our long term goal is to understand the developmental controls on cell cycle progression. We are taking a genetic approach by studying two mutants in C. elegans, cul-1 and lin-23, that have hyperplasia in multiple tissues. In these mutants, dividing cells ignore developmental cues and continue to proliferate. The extra cells generated are smaller than normal. We have cloned both the cul-1 and lin-23 genes. cul-1 and lin-23 are homologous to the S. cerevisiae genes CDC53 and CDC4, respectively, which are required for the G1 to S phase cell cycle transition. CDC53 and CDC4 are required for the ubiquitin-mediated degradation of cell cycle regulators, including cyclins and cyclin- dependent kinase inhibitors. An inability to degrade G1 cyclins in yeast produces a shorter G1 phase, small cells, and continued cell proliferation in the presence of inhibitory external signals. These phenotypes are similar to what is observed in cul-1 and lin-23 mutants. A compelling model is that cul-1 and lin-23 are required for the degradation of key cell cycle regulators in G1 phase, in particular G1 cyclins. The goals of the proposed research are to test this hypothesis and determine how cul-1 and lin-23 function to negatively regulate cell proliferation. In the first of three aims, we will determine the expression pattern of cul-1 and lin-23. We will test our hypothesis that cul-1 and lin-23 affect the protein levels of various cell cycle regulators by determining their expression and perdurance in wild type and cul-1 or lin-23 mutant strains. Further, we will determine whether cul-1 and lin-23 mutant strains have a shorter G1 phase. In the second aim, we will identify interacting proteins through the use of a yeast two-hybrid screen. Putative interacting clones will be analyzed by biochemical, cellular, and genetic approaches to determine their in vivo relevance. In the third aim, we will isolate and molecularly characterize extragenic suppressors of cul-1 and lin-23.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM055297-03
Application #
2872730
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1997-02-01
Project End
2002-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Georgia
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Athens
State
GA
Country
United States
Zip Code
30602
Starostina, Natalia G; Kipreos, Edward T (2012) Multiple degradation pathways regulate versatile CIP/KIP CDK inhibitors. Trends Cell Biol 22:33-41
Bosu, Dimple R; Feng, Hui; Min, Kyoengwoo et al. (2010) C. elegans CAND-1 regulates cullin neddylation, cell proliferation and morphogenesis in specific tissues. Dev Biol 346:113-26
Kim, Youngjo; Starostina, Natalia G; Kipreos, Edward T (2008) The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing. Genes Dev 22:2507-19
Kim, Jihyun; Kipreos, Edward T (2008) Control of the Cdc6 replication licensing factor in metazoa: the role of nuclear export and the CUL4 ubiquitin ligase. Cell Cycle 7:146-50
Kim, Jihyun; Feng, Hui; Kipreos, Edward T (2007) C. elegans CUL-4 prevents rereplication by promoting the nuclear export of CDC-6 via a CKI-1-dependent pathway. Curr Biol 17:966-72
Kim, Youngjo; Kipreos, Edward T (2007) The Caenorhabditis elegans replication licensing factor CDT-1 is targeted for degradation by the CUL-4/DDB-1 complex. Mol Cell Biol 27:1394-406
Kipreos, Edward T (2005) Ubiquitin-mediated pathways in C. elegans. WormBook :1-24
Brodigan, Thomas M; Liu, J i; Park, Morgan et al. (2003) Cyclin E expression during development in Caenorhabditis elegans. Dev Biol 254:102-15
Nayak, Sudhir; Santiago, Fernando E; Jin, Hui et al. (2002) The Caenorhabditis elegans Skp1-related gene family: diverse functions in cell proliferation, morphogenesis, and meiosis. Curr Biol 12:277-87
Kipreos, E T; Gohel, S P; Hedgecock, E M (2000) The C. elegans F-box/WD-repeat protein LIN-23 functions to limit cell division during development. Development 127:5071-82

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