Professor 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. Historically, we have focused 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. The cullin gene family contains five major branches in metazoa. Our laboratory has explored 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. CUL-2 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. More recently, we are focusing on understanding a role for the B-vitamin folates in stimulating the proliferation of germ stem cells in C. elegans. We have shown that this pathway functions independently of the normal role of folates in metabolism, and instead the folate initiates cell signaling through a pathway that involves the folate receptor. This research has implications for human cancers in which the folate receptor is overexpressed and promotes cancer progression. In our spare time, we also study simultaneity, which is the relativistic interaction of time and space. Our research uses available high-resolution optical data to assess the basic structure of spacetime and how it is relativistically altered in response to motion. Research Programs: Cells and Disease Cells in Development Cell Structure and Function Research Interests: Cellular biology; molecular genetics; regulation of cell division in Caenorhabditis elegans Selected Publications Peesapati, R.S., Austin-Byler, B.L., Nawaz, F.Z., Stevenson, J.B., Mais, S.A., Kaya, R.N., Hassan, M.G., Khanal, N., Wells, A.C., Ghiai, D., Garikapati, A.K., Selhub, J., and Kipreos, E. T. 2024. A specific folate activates serotonergic neurons to control C. elegans behaviour. Nature Communications 15: 8471. Rahman, M.M., Balachandran, R.S., Stevenson, J.B., Kim, Y., Proenca, R.B., Hedgecock, E.M., and Kipreos, E.T. 2023. The Caenorhabditis elegans cullin-RING ubiquitin ligase CRL4DCAF-1 is required for proper germline nucleolus morphology and male development. Genetics 225: iyad120. Nawaz, F. Z. and Kipreos, E. T. 2022. Emerging roles for folate receptor FOLR1 in signaling and cancer. Trends in Endocrinology & Metabolism 33: 159-174. Lin, R., Kipreos, E. T., Zhu, J., Khang, C. H., & Kner, P. 2021. Subcellular three-dimensional imaging deep through multicellular thick samples by structured illumination microscopy and adaptive optics. Nature Commmunications 12: 3148. Kipreos, E. T. and Balachandran, R. S. 2021. Optical data implies a null simultaneity test theory parameter in rotating frames. Modern Physics Letters A 36: 2150131. Kipreos, E. T. and Balachandran, R. S. 2021. Assessment of the relativistic rotational transformations. Modern Physics Letters A 36: 2150113. Kipreos, E. T. and van den Heuvel, S. 2019. Developmental control of the cell cycle: insights from C. elegans. Genetics 211: 797-829. Chaudhari, S. N. and Kipreos, E. T. 2018. The energy maintenance theory of aging: maintaining energy metabolism to allow longevity. BioEssays 40: e1800005. Chaudhari, S. N. and Kipreos, E. T. 2017. Increased mitochondrial fusion allows the survival of older animals in diverse C. elegans longevity pathways. Nature Communications 8: 182. Chaudhari, S.N., Mukherjee, M., Vagasi, A.S., Bi, G., Rahman, M.M., Nguyen, C.Q., Paul, L., Selhub, J., and Kipreos, E.T. 2016. Bacterial folates provide an exogenous signal for C. elegans germline stem cell proliferation. Developmental Cell 38: 33-46. Kipreos, E.T. and Balachandran, R.S. 2016. An approach to directly probe simultaneity. Modern Physics Letters A 31(26): 1650157. Balachandran, R.S., Heighington, C.S., Starostina, N.G., Anderson, J.W., Owen, D.L., Vasudevan, S., and Kipreos, E.T. 2016. The ubiquitin ligase CRL2(ZYG11) targets cyclin B1 for degradation in a conserved pathway that facilitates mitotic slippage. The Journal of Cell Biology 215: 151-166. 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. 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. Kipreos, E.T. 2005. C. elegans cell cycles: invariance and stem cell divisions. Nature Reviews Molecular Cell Biology 6: 766-776. 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. 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.
