Associate Professor, Department of Cell Biology
John S. Gammill Endowed Chair in Polycystic Kidney Disease, Warren Medical Research Institute
B.S., Pharmacy, Aristotle University, Greece
Ph.D., Pharmacology, University of Medicine and Dentistry, New Jersey
Project 1: Molecular and cellular basis of Autosomal Dominant Polycystic Kidney Disease
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases affecting more than half a million Americans and 12.5 million people, worldwide. It belongs to a group of pathological conditions called "ciliopathies" as they all seem to arise from defects in the assembly and/or function of the cilium, an antenna-like organelle protruding from the cell surface. Cilia are sensory organelles homing a large number of ion channels and receptors. Mutations in two genes, PKD1 and PKD2 are responsible for ADPKD. Their protein products, originally called PKD1 and PKD2 or polycystin-1 and 2 (currently named, TRPP2), respectively, are plasma membrane-spanning proteins present also in the primary cilium. It has been speculated that PKD1 and TRPP2 assemble into a receptor-channel complex linking extracellular stimuli to Ca2+ signaling. However, there are four major, yet unresolved questions that form the focus of our research interests: 1) what is the nature of the extracellular stimuli that activate the PKD1/TRPP2 receptor/channel complex? 2) How activation of PKD1 leads to the activation of TRPP2? 3) What are the downstream effectors of the PKD1/TRPP2 complex? 4) What is the role of the primary cilium in PKD2/TRPP2-based signaling? These questions are being investigated using complementary approaches in cell culture and the mouse.
Project 2: Role of primary cilia in cell division and development
While primary cilia are present in most quiescent mammalian cell types, they are never seen in mitosis. This observation has prompted investigators to propose that ciliogenesis and cell cycle progression are mutually exclusive processes. However, the mechanisms coordinating cilium biogenesis with the cell cycle have been a mystery for more than 30 years. We have recently identified Nde1 (nuclear distribution E homolog), as part of a network of proteins that mediates this coordination. Nde1 functions as a negative regulator of ciliary length. Consistent with such a role, Nde1 levels oscillate between high levels in mitosis and low levels in quiescence. Knockdown of Nde1 in cell culture and in zebrafish embryos leads to abnormally long cilia and a delay in the initiation of cell division. Embryonic defects induced by the loss of Nde1 include the random positioning of internal organs (left-right patterning defects) and the formation of abnormally small heads, which appears to be somewhat reminiscent to a human condition called microcephaly. Microcephaly is the main defect in mice lacking Nde1, while naturally occurring mutations in Nde1 have been reported in patients with schizophrenia. Using Nde1 as a model protein, we have been investigating how ciliogenesis is integrated with the cell cycle aiming at obtaining mechanistic insights into microcephaly and cancer.
Project 3: Role of TRP channel signaling in mesenchymal stem cells and bone architecture
The adult bone marrow contains a pool of multipotent stem cells that can give rise to osteoblasts (bone cells), adipocytes (fat cells), chondrocytes (cartiladge cells), cells forming the tendons, skin cells, and muscle cells. These cells are called mesenchymal stem cells or multipotent stromal cell (MSCs). Understanding the cellular mechanisms by which MSCs follow these distinct cell fates is fundamental in tissue repair in diseases associated with skeletal and muscular defects, obesity and diabetes. We have discovered a new role of Ca2+ ions in affecting the differentiation of progenitor MSCs to mature osteoblasts. Specifically, we found that the Ca2+-permeable TRPC1 ion channel suppresses the differentiation of MSCs to mature osteoblasts. I-mfa, which is a TRPC1-associated protein, inhibits TRPC1 activity. We are currently using Trpc1-/-, I-mfa-/-, and Trpc1-/-;I-mfa-/- mice to investigate the mechanism by which TRPC1 and I-mfa work in concert to regulate the formation of adult osteoblasts and bone architecture, in general. Successful completion of this project could set the stage for new approaches to combat osteoporosis and other diseases associated with bone loss.
SELECTED PUBLICATIONS: 1) Kim S., Zaghloul NA., Bubenshchikova E., Oh EC., Rankin S., Katsanis N., Obara T., and Tsiokas L.Nde-1 mediated suppression of ciliogenesis affects cell cycle re-entry. Nature Cell Biology, 13(4): 351-60, 2011.
"New and Views" http://www.nature.com/ncb/journal/v13/n4/pdf/ncb0411-340.pdf
2) Bai CX., Kim S., Li WP., Streets AJ., Ong AC., and Tsiokas L. Activation of TRPP2 through mDia1-dependent voltage gating. EMBO Journal, 27: 1345-1356, 2008.
3) Bai CX., Giamarchi A., Rodat-Despoix L., Padilla F., Downs T., Tsiokas L.,* and Delmas P.* Formation of a novel receptor-operated channel by heteromeric assembly of TRPP2 and TRPC1 subunits. EMBO Reports, 9:472-9, 2008.
4) Tsiokas, L., Kim, S., and Ong, EC. Cell biology of Polycystin-2 (invited review). Cellular Signalling, 19: 444-453, 2007.
5) Ma, R., Li, W. P., Rundle, D., Kong, J., Akbarali, H., and Tsiokas, L. PKD2 functions as an Epidermal Growth Factor-activated plasma membrane channel. Molecular and Cellular Biology 25(18): 8285-98, 2005.
featured article at Science's STKE:
6) Rundle, D., Gorbsky, G. J., and L. Tsiokas. PKD2 interacts and co-localizes with mDia1 to mitotic spindles of dividing cells: Role of mDia1 in PKD2 localization to the mitotic spindles. Journal of Biological Chemistry 279(28): 29728-39, 2004.
7) Ma, R., Rundle, D., Jacks, J., Koch, M., Downs, T., and L. Tsiokas. Inhibitor of myogenic family, a novel suppressor of store-operated currents through an interaction with TRPC1. Journal of Biological Chemistry 278: 52763-52772, 2003.
8) Hanaoka, K., Qian, F., Boletta, A., Bhunia, A., Piontek, K., Tsiokas, L., Sukhatme, V. P., Guggino, W. B., and Germino, G. G. Co-assembly of polycystin-1 and-2 produces unique cation-permeable currents.Nature 408: 990-994, 2000.
9) Tsiokas, L., Arnould, T., Zhu, C., Kim, Walz, G., and V.P. Sukhatme. Specific association of the gene product of PKD2 with the TRPC1 channel. Proceedings of the National Academy of Sciences (USA) 96: 3934-3939, 1999.
10) Tsiokas, L., Kim, E., Arnould, T., Sukhatme, V. P. and G. Walz. Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2. Proceedings of the National Academy of Sciences (USA) 94: 6965-6970, 1997.
University of Oklahoma Health Sciences Center
Stanton L. Young Biomedical Research Center
975 10th Ave NE
Oklahoma City, OK 73126-0901
Phone: (405) 271-8001 ext. 46211
Fax: (405) 271-3548
CV - Leonidas Tsiokas, Ph.D.