Beth S. Lee, Ph.D.

Associate Professor 017 Hamilton Hall (office) 004/012 Hamilton Hall (labs) 1645 Neil Avenue Columbus  OH  43210-1218 lee.2076@osu.edu

Education:
Ph.D., Microbiology, Stanford University, Stanford, CA

Research Interests:
The Lee lab has a wide variety of interests in renal and bone cell biology. Our recent work has ranged from the study of gene expression by transcriptional and post-transcriptional mechanisms to cytoskeletal dynamics to ion transporters. Currently, our work focuses on two major topics. The first of these is regulation of mRNA stability in renal epithelial cells during ischemia-reperfusion injury, while the second is the role of actin binding proteins (specifically myosins and tropomyosins) in regulating osteoclast function. This work is supported by two awards from the NIH:

·   RO1 DK052131: Regulation of mRNA Stability in Kidney Epithelia, NIH/NIDDK; 1997-2010

·   RO1 AR051515: Dynamics of the Actin Cytoskeleton in Osteoclasts, NIH/NIAMS; 2006-2010

Project 1, regulation of mRNA stability:  We are investigating the role of the RNA binding protein HuR in protection of kidney epithelial cells from ischemia-reperfusion injury. HuR binds to and stabilizes a subset of cellular mRNAs that contain AU- or U-rich sequences. We found that when cells undergo the stress of ischemic injury or ATP depletion, HuR translocates from the nucleus to the cytoplasm to bind these mRNAs and protect them from degradation; further its own expression is increased by transcriptional and translational mechanisms to help protect the cells from future insults. We are using both in vivo and in vitro models of ischemic stress to understand how HuR expression and function is regulated.

Project 2, actin dynamics in osteoclasts:  Osteoclasts are large multinucleated cells derived from fusion of monocyte-macrophage lineage precursors. These cells degrade bone in an effort to maintain skeletal health and regulate serum calcium levels. However, too much or too little osteoclast activity can result in skeletal disorders such as osteoporosis or osteopetrosis. Because osteoclasts are highly motile cells that polarize and depolarize in the process of bone resorption, they possess an unusually dynamic actin cytoskeleton and express unique matrix attachment complexes. We are focusing on the role of two actin binding protein classes, myosins and tropomyosins, in regulating osteoclast function.

Myosins are actin-activated motor proteins that perform a wide variety of cellular functions, from cell division to motility to intracellular vesicle transport. We are in the process of surveying the complement of myosin isoforms in osteoclasts. Through loss-of-function and gain-of-function methodologies, we have identified one isoform involved patterning of adhesion complexes, and found that expression of another is proteolytically regulated during osteoclastogenesis to permit osteoclast precursor fusion. Tropomyosins are rod-shaped proteins that bind actin filaments and stabilize them by regulating accession of other actin modifying proteins to the filament. We found that osteoclasts express at least eight tropomyosin isoforms, and have found some of these to be involved in regulation of adhesion complexes and support of the internal scaffolding of osteoclasts. We are continuing these studies to determine the role of other myosin and tropomyosin isoforms and to determine the mechanisms by which they exert their functions.

Laboratory Members:
Dina Ayupova, Postdoctoral Researcher
Brooke Trinrud McMichael, Postdoctoral Researcher
Preeyal Kotadiya, Graduate Student (IBGP)
Mamata Singh, Graduate Student (OSBP)
Suman Govindaraju, Graduate Student (OSBP)
Tejdeep Singh, Undergraduate Researcher

Representative Publications:
• Kotadiya P, McMichael BK, Lee BS. High molecular weight tropomyosins regulate osteoclast cytoskeletal morphology. Bone, in press, 2008.
• McMichael BK, Lee BS. Tropomyosin 4 regulates adhesion structures and resorptive capacity in osteoclasts. Exp Cell Res 314:564-573, 2008.
• McMichael B, Kotadiya P, Holliday LS, Lee BS. Tropomyosin isoforms localize to distinct microfilament populations in osteoclasts. Bone 39(4):694-705, 2006.
• Jeyaraj S, Dakhlallah D, Hill SR, Lee BS. Expression and distribution of HuR during ATP depletion and recovery in proximal tubule cells. Am J Physiol-Renal Physiol 291:F1255-F1263, 2006.
• Jeyaraj S, Dakhlallah D, Hill SR, Lee BS. HuR stabilizes V-ATPase mRNA during cellular energy depletion. J Biol Chem 280(45):37957-37964, 2005.
• Chen S-H, Bubb MR, Yarmola EG, Zuo J, Jiang J, Lee BS, Lu M, Gluck SL, Hurst IR, Holliday LS. Vacuolar H⁺-ATPase binding to microfilaments: regulation in response to phosphatidylinositol 3-kinase activity and detailed characterization of the actin binding site in subunit B. J Biol Chem 279(9):7988-7998, 2004.
• Gupta A, Lee BS, Khadeer MA, Tang Z, Chellaiah M, Abu-amer Y, Goldknopf J, Hruska KA. Leupaxin is a critical adaptor protein in the adhesion zone of the osteoclast. J Bone Miner Res 18(4):669-685, 2003.
• Wang SP, Krits I, Bai S, Lee BS. Regulation of enhanced vacuolar H⁺-ATPase expression in macrophages. J Biol Chem 277(11):8827-8834, 2002.
• Krits I, Wysolmerski RB, Holliday LS, Lee BS. Differential localization of myosin II isoforms in resting and activated osteoclasts. Calcif Tissue Int 71(6):530-538, 2002.