Regulation of Cell Differentiation by ssDNA/RNA-Binding Proteins
Dr. Kelm received his Ph.D. in Biochemistry from the University of Vermont College of Medicine in 1991. Upon completion of his Ph.D. studies, he joined Haematologic Technologies, Inc. as a Scientist and was later appointed Director of Assay Development. Dr. Kelm returned to academia in late 1994 as a Research Fellow in the Department of Biochemistry and Molecular Biology at the Mayo Clinic to pursue research involving single-stranded DNA/mRNA-binding proteins. In October 2001, Dr. Kelm joined the UVM faculty as an Assistant Professor in the Department of Medicine. In January 2002, he was appointed as an adjunct Assistant Professor in the Department of Biochemistry. Dr. Kelm was promoted to Associate Professor with tenure in July 2006.
My research group is interested in understanding the molecular mechanisms that lead to phenotypic reprogramming of disease or injury-activated cell types of the heart, lung, and blood vessels. This line of investigation has led us to identify several members of the Pur and Y-box families of single-stranded DNA (ssDNA)/RNA-binding proteins as crucial regulators of muscle gene expression in myofibroblasts, smooth muscle cells, and cardiomyocytes. Our scientific approach is to apply rigorous techniques of physical biochemistry in conjunction with cell-and tissue-based bioassays to test putative models of transcriptional and translational repression by Pur α, Pur β, and YB-1. In vitro experiments are designed to yield quantitative information describing the structural and functional properties of each protein in relation to ssDNA/RNA recognition, gene regulation, and the modulation of cell phenotype. In vivo studies are focused on establishing the physiological role(s) of these unique ssDNA/RNA-binding proteins in mouse models of cardiovascular disease or injury. Over the past 12 years, our work has been supported by grants from the NHLBI and AHA.
Conceptual model of transcriptional repression by sequence-specific ssDNA-binding proteins. Adapted from Carlini et el. J Biol Chem 277:8682-8692, 2002.
David JJ, Subramanian SV, Zhang A, Willis WL, Kelm RJ Jr, Leier CV, Strauch AR. Y-box binding protein-1 implicated in translational control of fetal myocardial gene expression after cardiac transplant. Exp Biol Med (Maywood). 2012 May 1;237(5):593-607
Gurha P, Abreu-Goodger C, Wang T, Ramirez MO, Drumond AL, van Dongen S, Chen Y, Bartonicek N, Enright AJ, Lee B, Kelm RJ Jr, Reddy AK, Taffet GE, Bradley A, Wehrens XH, Entman ML, Rodriguez A. Targeted deletion of microRNA-22 promotes stress-induced cardiac dilation and contractile dysfunction. Circulation. 2012 Jun 5;125(22):2751-2761
Rumora AE, Steere AN, Ramsey JE, Knapp AM, Ballif BA, Kelm RJ Jr. Isolation and characterization of the core single-stranded DNA-binding domain of purine-rich element binding protein B (Purβ). Biochem Biophys Res Commun. 2010 Sep 24;400(3):340-345
van Rooij E, Quiat D, Johnson BA, Sutherland LB, Qi X, Richardson JA, Kelm RJ Jr, Olson EN. A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance. Dev Cell. 2009 Nov;17(5):662-673
Ramsey JE, Kelm RJ Jr. Mechanism of strand-specific smooth muscle α-actin enhancer interaction by purine-rich element binding protein B (Purβ). Biochemistry. 2009 Jul 14;48(27):6348-6360
Zhang A, David JJ, Subramanian SV, Liu X, Fuerst MD, Zhao X, Leier CV, Orosz CG, Kelm RJ Jr, Strauch AR. Serum response factor neutralizes Pur alpha- and Pur beta-mediated repression of the fetal vascular smooth muscle alpha-actin gene in stressed adult cardiomyocytes. Am J Physiol Cell Physiol. 2008 Mar;294(3):C702-714
Knapp AM, Ramsey JE, Wang SX., Strauch AR, Kelm RJ Jr. Structure-function analysis of mouse Pur beta II: Conformation altering mutations disrupt single-stranded DNA and protein interactions crucial to smooth muscle alpha-actin gene repression. J Biol Chem. 2007 Dec 7;282(49):35899-35909
* indicates equal contribution
Hariharan S, Kelm RJ Jr, Strauch AR (2014) The Purα / Purβ Single-Strand DNA-Binding Proteins Attenuate Smooth-Muscle Actin Gene Transactivation in Myofibroblasts. J Cell Physiol in press.
Rumora AE, Wang SX, Ferris LA, Everse SJ, Kelm RJ Jr (2013) Structural basis of multisite single-stranded DNA recognition and ACTA2 repression by purine-rich element binding protein B (Purβ). Biochemistry 52(26): 4439-50.
David JJ, Subramanian SV, Zhang A, Willis WL, Kelm RJ Jr, Leier CV, Strauch AR (2012) Y-box binding protein-1 implicated in translational control of fetal myocardial gene expression after cardiac transplant. Exp Biol Med (Maywood) 237(5): 593-607.
Gurha P, Abreu-Goodger C, Wang T, Ramirez MO, Drumond AL, van Dongen S, Chen Y, Bartonicek N, Enright AJ, Lee B, Kelm RJ Jr, Reddy AK, Taffet GE, Bradley A, Wehrens XH, Entman ML, Rodriguez A (2012) Targeted deletion of microRNA-22 promotes stress-induced cardiac dilation and contractile dysfunction. Circulation 125(22): 2751-61.
Rumora AE, Steere AN, Ramsey JE, Knapp AM, Ballif BA, Kelm RJ Jr (2010) Isolation and characterization of the core single-stranded DNA-binding domain of purine-rich element binding protein B (Purβ). Biochem Biophys Res Commun 400(3): 340-5.
French CJ, Zaman AK, Kelm RJ Jr, Spees JL, Sobel BE (2010) Vascular rhexis: loss of integrity of coronary vasculature in mice subjected to myocardial infarction. Exp Biol Med (Maywood) 235(8): 966-73.
Kollander R, Solovey A, Milbauer LC, Abdulla F, Kelm RJ Jr, Hebbel RP (2010) Nuclear factor-kappa B (NFkappaB) component p50 in blood mononuclear cells regulates endothelial tissue factor expression in sickle transgenic mice: implications for the coagulopathy of sickle cell disease. Transl Res 155(4): 170-7.
Department of Medicine
Office: CRF 165
Lab: CRF 169
Lauren Ferris, Biochem Grad Student
Amy Rumora, Biochem Grad Student
- 4/21/2015 11:30 AM – 12:30 PM
- 4/28/2015 11:30 AM – 12:30 PM
- 5/5/2015 11:30 AM – 12:30 PM
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