Our laboratory is interested in understanding how the cell cycle is regulated in the context of organismal development. We are using the nematode Caenorhabditis elegans as a model system. The adult C. elegans has only 959 somatic cells, yet has multiple tissues, including muscle, skin, neurons, and intestine. Somatic cell divisions are developmentally programmed and largely invariant, thereby allowing detailed analysis of individual cell divisions through development.
We are currently focusing on understanding the functions of the cullin/RING finger class of ubiquitin-protein ligases, whose members target the ubiquitin-mediated degradation of a diverse set of substrates, including cell cycle regulators. Cullin/RING finger complexes comprise a core that includes cullins and RING finger proteins. The cullin gene family contains five major branches in metazoa. Our laboratory is currently exploring the in vivo functions of the C. elegans cullins CUL-1, CUL-2, and CUL-4. CUL-1 functions as a negative cell cycle regulator, which is required for cell cycle exit. In the absence of CUL-1, dividing cells are unable to respond to developmental cues to exit the cell cycle, and instead continue to proliferate thereby producing hyperplasia. CUL-2, in contrast, is a positive cell cycle regulator that is required for a number of different cell cycle events: G1 phase progression, chromatin condensation, and mitotic and meiotic progression. Finally, CUL-4 functions as a negative regulator of DNA replication that acts to restrict DNA replication licensing.
Our current projects involve both genetic and biochemical approaches to identify the substrates that must be ubiquitinated to allow the cullin-dependent cell cycle events to occur. We are also characterizing the proteins components in the cullin/RING finger complexes that are responsible for the observed cellular functions, as we expect multiple substrate-binding components will be present for each core complex. These studies on understanding basic aspects of cell cycle regulation will help to lay the foundation for the more long-range, comprehensive goal of understanding of how the cell cycle is regulated through development.
Starostina, N.G., Simpliciano, J.M., McGuirk, M.A., and Kipreos, E.T. 2010. CRL2LRR-1 targets a CDK inhibitor for cell cycle control in C. elegans and actin-based motility regulation in human cells. Developmental Cell, 19: 753-756.
Akella, J.S., Wloga, D., Kim, J. Starostina, N.G., Lyons-Abbott, S., Morrissette, N.S., Dougan, S.T., Kipreos, E.T., and Gaertig, J. 2010. MEC-17 is an alpha-tubulin acetyltransferase. Nature, 467: 218-22.
Bosu, D.R., Feng, H., Min, K., Kim, Y., and Kipreos, E.T. 2010. C. elegans CAND-1 regulates cullin neddylation and regulates cell proliferation and morphogenesis in specific tissues. Developmental Biology, 346: 113-26.
Kim, Y., Starostina, N.G., and Kipreos, E.T. 2008. The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing. Genes & Development 22: 2507-2519. Starostina, N.G., Lim, J., Schvarzstein, M., Wells, L., Spence, A.M., and Kipreos, E.T. 2007. A CUL-2 ubiquitin ligase containing three FEM proteins degrades TRA-1 to regulate C. elegans sex determination. Developmental Cell 13: 127-139.
Kim, J., Feng, H., and Kipreos, E.T. 2007. C. elegans CUL-4 prevents re-replication by promoting the nuclear export of CDC-6 via a CKI-1-dependent pathway. Current Biology 17: 966-972. Vasudevan, S., Starostina, N.G., and Kipreos, E.T. 2007. The C. elegans cell cycle regulator ZYG-11 defines a conserved family of CUL-2 complex components. EMBO Reports 8: 279-286.
Kim, Y., and Kipreos, E.T. 2007. The C. elegans replication licensing factor CDT-1 is targeted for degradation by the CUL-4/DDB-1 complex. Molecular and Cellular Biology 27: 1394-1406.
Kipreos, E.T. 2005. C. elegans cell cycles: invariance and stem cell divisions. Nature Reviews Molecular Cell Biology 6: 766-776.
Liu, J., Vasudevan, S., and Kipreos, E.T. 2004. CUL-2 and ZYG-11 promote meiotic anaphase II and the proper placement of the anterior-posterior axis in C. elegans. Development 131: 3513-3525.
Zhong, W., H. Feng, F.E. Santiago, and Kipreos, E.T. 2003. CUL-4 ubiquitin ligase maintains genome stability by restraining DNA replication licensing. Nature 423: 885-889.
Nayak S., F. Santiago, H. Jin, D. Lin, T. Schedl, and Kipreos, E.T. 2002. The Caenorhabditis elegans Skp1-related (skr) gene family: diverse functions in cell proliferation, morphogenesis, and meiosis. Current Biology 12: 277-287.
Liu, J. and Kipreos, E.T. 2000. Evolution of cyclin-dependent kinases (CDKs) and CDK-activating kinases (CAKs): Differential conservation of CAKs in yeast and metazoa. Molecular Biology and Evolution 17: 1061-1074.
Feng, H., W. Zhong, G. Punkosdy, S. Gu, L. Zhou, E.K. Seabolt, and Kipreos, E.T. 1999. CUL-2 is required for the G1-to-S phase transition and mitotic chromosome condensation in Caenorhabditis elegans. Nature Cell Biology 1: 486-492.