William E. Russell, M.D.
Cornelius Vanderbilt Professor of Pediatrics
Professor of Cell & Developmental Biology
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Vanderbilt University Medical Center, Division of Pediatric Endocrinology
11136 Doctors Office Tower, 2200 Childrens Way
Nashville, TN 37232-9170
- M.D. - Harvard University, 1976
- Fellowship - University of North Carolina Health Care System, 1984
- Fellowship - Massachusetts General Hospital, 1982
- Residency - Massachusetts General Hospital, 1979
- Internship - Massachusetts General Hospital, 1977
The principal focus of the laboratory is to define the mechansims, both stimulatory and inhibitory, that control the regeneration of liver. The regenerating liver is used as a model in which to study the cellular and molecular mechanisms of growth control in a normal, non-neoplastic tissue. The critical issues to be understood in the process are: which signals sense the acute loss of liver mass and initiate regenerative growth; which signals maintain the differentiated functions of the liver during proliferation, and which signals stop liver growth when it has reached its appropriate mass? We aim to identify the major signals that regulate regeneration, the cells and tissues in which they are generated, and the nature of the cellular and molecular cross-talk that controls them. We study these problems in whole animals, some genetically modified to overexpress or block critical regulatory molecules, and others treated with growth factors or neutralizing antibodies; in primary cultures and lines of hepatocytes and other liver-derived cells; and in subcellular fractions of cells.
A major focus in the lab is the role of EGF-like molecules in liver growth and metabolism.
Although a potent hepatic mitogen, EGF was reported long ago to have actions that both mimic and antagonize those of insulin in the liver. The EGF receptor (EGFr) is one of a family of four related tyrosine kinase receptors: EGFr, ErbB2, ErbB3, and ErbB4. Ligands of these receptors induce hetero- and homodimers and divergent downstream signaling. Adult liver expresses only EGFr and ErbB3, while fetal liver expresses EGFr, ErbB2 and ErbB3. Ligands of both the EGFr (TGFalpha, amphiregulin, epiregulin, betacellulin, and HB-EGF) and ErbB3 (heregulins or neuregulins) are expressed in liver or pancreas. The laboratory is actively investigating the proliferative and metabolic signals generated by this important system.
ErbB2, which can dimerize with either EGFr or ErbB3 is strongly expressed in fetal and neonatal liver, but is extinguished around the time of weaning, suggesting it to be a developmental switch. The model under investigation is that the ErbB receptor family transduces growth and metabolic signals in the liver, and perhaps in other tissues, and that the various ligands and receptors in this family have different actions at different developmental stages. In addition to developmental differences in ErbB receptor expression, there are also striking zonal and circadian differences in their expression, adding to the potential richness and subtlety of ErbB signaling in the liver.
Other areas of active investigation in the laboratory include the role of receptor guanylyl cyclases, the plasminogen activator system, and also of growth inhibitors in the development and regeneration of liver.
Endocrine disorders of children from birth through adolescence.
- Rosenbloom, ST, Qi, X, Riddle, WR, Russell, WE, Donlevy, SC, Giuse, D, Sedman, AB, Spooner, SA Implementing Pediatric Growth Charts into an Electronic Health Record System. J Am Med Inform Assoc, 2006.
- Romero-Gallo, J, Sozmen, EG, Chytil, A, Russell, WE, Whitehead, R, Parks, WT, Holdren, MS, Her, MF, Gautam, S, Magnuson, M, Moses, HL, Grady, WM Inactivation of TGF-beta signaling in hepatocytes results in an increased proliferative response after partial hepatectomy. Oncogene, 24(18), 3028-41, 2005.
- Hinkle, CL, Sunnarborg, SW, Loiselle, D, Parker, CE, Stevenson, M, Russell, WE, Lee, DC Selective roles for tumor necrosis factor alpha-converting enzyme/ADAM17 in the shedding of the epidermal growth factor receptor ligand family: the juxtamembrane stalk determines cleavage efficiency. J Biol Chem, 279(23), 24179-88, 2004.
- Lee, DC, Sunnarborg, SW, Hinkle, CL, Myers, TJ, Stevenson, MY, Russell, WE, Castner, BJ, Gerhart, MJ, Paxton, RJ, Black, RA, Chang, A, Jackson, LF TACE/ADAM17 processing of EGFR ligands indicates a role as a physiological convertase. Ann N Y Acad Sci, 99522-38, 2003.
- Carver, RS, Stevenson, MC, Scheving, LA, Russell, WE Diverse expression of ErbB receptor proteins during rat liver development and regeneration. Gastroenterology, 123(6), 2017-27, 2002.
- Scheving, Lawrence A, Stevenson, Mary C, Taylormoore, Jonathan M, Traxler, Peter, Russell, William E Integral role of the EGF receptor in HGF-mediated hepatocyte proliferation. Biochem Biophys Res Commun, 290(1), 197-203, 2002.
- Mathew, Revi P, Najjar, Jennifer L, Lorenz, Rodney A, Mayes, Darrel E, Russell, William E Premature pubarche in girls is associated with functional adrenal but not ovarian hyperandrogenism. J Pediatr, 141(1), 91-8, 2002.
- Sunnarborg, SW, Hinkle, CL, Stevenson, M, Russell, WE, Raska, CS, Peschon, JJ, Castner, BJ, Gerhart, MJ, Paxton, RJ, Black, RA, Lee, DC Tumor necrosis factor-alpha converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability. J Biol Chem, 277(15), 12838-45, 2002.
- Scheving, L A, Russell, W E Insulin and heregulin-beta1 upregulate guanylyl cyclase C expression in rat hepatocytes: reversal by phosphodiesterase-3 inhibition. Cell Signal, 13(9), 665-72, 2001.
- NIH Consensus Development Panel "Osteoporosis Prevention, Diagnosis, and Therapy." JAMA, 285785-795, 2001.
- Mauras N, Attie KM, Reiter EO, Saenger P, Baptista J, and the Genentech, Inc., Cooperative Study Group "High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: randomized, multicenter trial." J. Clin Endocrinol Metab, 853653-3660, 2000.
- Busse, D, Doughty, R S, Ramsey, T T, Russell, W E, Price, J O, Flanagan, W M, Shawver, L K, Arteaga, C L Reversible G(1) arrest induced by inhibition of the epidermal growth factor receptor tyrosine kinase requires up-regulation of p27(KIP1) independent of MAPK activity. J Biol Chem, 275(10), 6987-95, 2000.
- Busse D, Doughty RS, Ramsey TT, Russell WE, Price JO, Flanagan WM, Shawver LK, and Arteaga CL "Reversible G1 arrest induced by inhibition of the EGF receptor tyrosine kinase requires up-regulation of p27KIP1 independent of MAPK activity." J. Biol. Chem., 2756987-6995, 2000.
- Carver RS, Russell WE "A diversity of EGF-like ligands and receptors in liver." Fleig W (ed). Normal and Malignant Liver Cell Growth-Falk Workshop Kluwer Academic Publishers, 33-46, 1999.
- Roselli HC, Su M, Washington K, Kerins DM, Vaughan DE, Russell WE "Liver regeneration is delayed in urokinase- deficient mice. Am J Physiol (GI and Liver Physiol 38)." , 275G1472-G1479, 1998.
- Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC, Russell WE, Castner BJ, Johnson RS, Fitzner JN, Boyce RW, Nelson N, Kozlosky CJ, Wolfson MF, Rauch CT, Cerretti DP, Paxton RJ, March CJ, Black RA "An essential role for ectodomain shedding mammalian development." Science , 2821281-1284, 1998.
- Peschon, JJ, Slack, JL, Reddy, P, Stocking, KL, Sunnarborg, SW, Lee, DC, Russell, WE, Castner, BJ, Johnson, RS, Fitzner, JN, Boyce, RW, Nelson, N, Kozlosky, CJ, Wolfson, MF, Rauch, CT, Cerretti, DP, Paxton, RJ, March, CJ, Black, RA An essential role for ectodomain shedding in mammalian development. Science, 282(5392), 1281-4, 1998.
- Roselli, H T, Su, M, Washington, K, Kerins, D M, Vaughan, D E, Russell, W E Liver regeneration is transiently impaired in urokinase-deficient mice. Am J Physiol, 275(6 Pt 1), G1472-9, 1998.
- Russell WE, Carver RS "The EGF/TGF family of growth factors and their receptors." Strain AJ, andDiehl AM (eds) Liver Growth and Repair: From Basic Science to Clinical Practice. London: Chapman & Hall, Ltd., 185-218, 1998.
- Carver RS, Mathew PM, Russell WE "Hepatic expression of ErbB3 is repressed by insulin in a pathway sensitive to PI-3 kinase inhibitors." Endocrinology, 1385195-5201, 1997.
- Carver, R S, Mathew, P M, Russell, W E Hepatic expression of ErbB3 is repressed by insulin in a pathway sensitive to PI-3 kinase inhibitors. Endocrinology, 138(12), 5195-201, 1997.
- Berkowitz EA, Seroogy KB, Schroeder JA, Russell WE, Evans EP, Riedel RF, Phillips HK, Harrison CA, Lee DC, Luetteke NC "Characterization of the mouse TGF gene: its expression during eyelid development and in waved-1 tissues." Cell Growth & Diff, 71271-1282, 1996.
- Berkowitz, EA, Seroogy, KB, Schroeder, JA, Russell, WE, Evans, EP, Riedel, RF, Phillips, HK, Harrison, CA, Lee, DC, Luetteke, NC Characterization of the mouse transforming growth factor alpha gene: its expression during eyelid development and in waved 1 tissues. Cell Growth Differ, 7(9), 1271-82, 1996.
- Scheving, L.A., Russell, W.E "Guanylyl cyclase C is up-regulated by nonparenchymal cells and hepatocytes in regenerating rat liver." Cancer Research , 565186-5191, 1996.
- Scheving, L A, Russell, W E Guanylyl cyclase C is up-regulated by nonparenchymal cells and hepatocytes in regenerating rat liver. Cancer Res, 56(22), 5186-91, 1996.
- Carver, R. S., Sliwkowski, M. X., Sitaric, S., Russell, W. E "Insulin regulates ErbB3 and heregulin binding in rat hepatocytes." J. Biol. Chem., 27113491-13496, 1996.
- Carver, R S, Sliwkowski, M X, Sitaric, S, Russell, W E Insulin regulates heregulin binding and ErbB3 expression in rat hepatocytes. J Biol Chem, 271(23), 13491-6, 1996.
- Russell, W. E., Kaufmann, W. K., Sitaric, S., Luetteke, N. C., Lee, D. C "Liver regeneration and hepatocarcinogenesis in TGFalpha targeted mice." Molecular , 15183-189, 1996.
- Russell, W E, Kaufmann, W K, Sitaric, S, Luetteke, N C, Lee, D C Liver regeneration and hepatocarcinogenesis in transforming growth factor-alpha-targeted mice. Mol Carcinog, 15(3), 183-9, 1996.
- Scheving LA, Russell WE, Chong K-M "Structure, glycosylation and localization of rat intestinal heat-stable enterotoxin receptor/guanylyl cyclase C: Modulation by fasting." Am J Physiol (Gastrointest Liver Physiol 34), 271G959-968, 1996.
- Scheving, L A, Russell, W E, Chong, K M Structure, glycosylation, and localization of rat intestinal guanylyl cyclase C: modulation by fasting. Am J Physiol, 271(6 Pt 1), G959-68, 1996.
- Duddy, SK, Earp, HS, Russell, WE, Smith, GJ, Grisham, JW Differential dependence of the tumorigenicity of chemically transformed rat liver epithelial cells on autocrine production of transforming growth factor alpha. Cell Growth Differ, 6(3), 251-61, 1995.
- Duddy SK, Earp HS, Russell WE, Smith GJ, Grisham JW "Differential dependence of the tumorigenicity of chemically transformed rat liver epithelial cells on autocrine production of transforming growth factor alpha." Cell Growth & Differentiation , 251-2611995.
- Barnard, J A, Beauchamp, R D, Russell, W E, Dubois, R N, Coffey, R J Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology. Gastroenterology, 108(2), 564-80, 1995.
- Russell, WE Protect your assets from future claims. CDS Rev, 86(4), 14-5, 1993.
- Russell WE, Dempsey PJ, Sitaric S, Peck AJ, Coffey Jr, RJ "Transforming growth factor- concentrations increase in regenerating rat liver: Evidence for a delayed accumulation of mature TGF-." Endocrinology , 1331731-1738, 1993.
- Russell, W E, Dempsey, P J, Sitaric, S, Peck, A J, Coffey, R J Transforming growth factor-alpha (TGF alpha) concentrations increase in regenerating rat liver: evidence for a delayed accumulation of mature TGF alpha. Endocrinology, 133(4), 1731-8, 1993.
- Polk, W H, Dempsey, P J, Russell, W E, Brown, P I, Beauchamp, R D, Barnard, J A, Coffey, R J Increased production of transforming growth factor alpha following acute gastric injury. Gastroenterology, 102(5), 1467-74, 1992.
- Millard WJ, Romano TO, Layden MP, Russell WE, Martin RJ "Growth hormone secretion in the obese male rat: Modulation by the gonadal and thyroid axes." Growth Dev & Aging , 5591-103, 1991.
- Millard, WJ, Romano, TM, Layden, MP, Russell, WE, Martin, RJ Growth hormone secretion in the obese male rat: modulation by the gonadal and thyroid axes. Growth Dev Aging, 55(2), 91-103, 1991.
- Donaghue, KC, Badger, TM, Millard, WJ, Frisch, LS, Russell, WE Absence of ultradian rhythm or diurnal variation in insulin-like growth factor-I in rats. Neuroendocrinology, 52(1), 1-8, 1990.
- Donaghue KC, Badger TO, Millard WJ, Frisch LS, Russell WE "Absence of ultradian rhythm or diurnal variation in insulin-like growth factor-I (IGF-I) in rats." Neuroendocrinol, 521-8, 1990.
- Cunningham, JJ, Lydon, MK, Russell, WE Calorie and protein provision for recovery from severe burns in infants and young children. Am J Clin Nutr, 51(4), 553-7, 1990.
- Coffey, R J, Russell, W E, Barnard, J A Pharmacokinetics of TGF beta with emphasis on effects in liver and gut. Ann N Y Acad Sci, 593285-91, 1990.
- Maiter, DM, Gabriel, SM, Koenig, JI, Russell, WE, Martin, JB Sexual differentiation of growth hormone feedback effects on hypothalamic growth hormone-releasing hormone and somatostatin. Neuroendocrinology, 51(2), 174-80, 1990.
- Smith, EP, Russell, WE, French, FS, Wilson, EM A form of basic fibroblast growth factor is secreted into the adluminal fluid of the rat coagulating gland. Prostate, 14(4), 353-65, 1989.
- Gabriel, SM, Millard, WJ, Koenig, JI, Badger, TM, Russell, WE, Maiter, DM, Martin, JB Sexual and developmental differences in peptides regulating growth hormone secretion in the rat. Neuroendocrinology, 50(3), 299-307, 1989.
- Russell WE "Transforming growth factor beta (TGF-?) inhibits hepatocyte DNA synthesis independent of EGF binding and EGF receptor phosphorylation." J Cell Physiol, 135253-261, 1988.
- Russell, WE Transforming growth factor beta (TGF-beta) inhibits hepatocyte DNA synthesis independently of EGF binding and EGF receptor autophosphorylation. J Cell Physiol, 135(2), 253-61, 1988.
- Lin, SH, Russell, WE Two Ca2+-dependent ATPases in rat liver plasma membrane. The previously purified (Ca2+-Mg2+)-ATPase is not a Ca2+-pump but an ecto-ATPase. J Biol Chem, 263(25), 12253-8, 1988.
- Lin S-H, Russell WE "Two Ca2+-dependent ATPases in rat liver plasma membrane: The previously purified Ca2+(Mg2+)- ATPase is not a Ca2+-pump but an ecto-ATPase." J Biol Chem , 26312253-12258, 1988.
- Russell WE, Coffey RJ, Jr, Ouellette AJ, Moses HL "Type ? transforming growth factor reversibly inhibits the early proliferative response to partial hepatectomy in the rat." Proc Natl Acad Sci USA, 855126-5130, 1988.
- Russell, WE, Coffey, RJ, Ouellette, AJ, Moses, HL Type beta transforming growth factor reversibly inhibits the early proliferative response to partial hepatectomy in the rat. Proc Natl Acad Sci U S A, 85(14), 5126-30, 1988.
- Cleveland, RH, Kushner, DC, Russell, WE, Herman, TE, Kim, SH, Crawford, J Lipoid cell tumor of the ovary: a cause of virilization in girls. Am J Dis Child, 141(7), 716-8, 1987.
- Coughlin, JP, Austen, WG, Donahoe, PK, Russell, WE Liver regeneration during immunosuppression. J Pediatr Surg, 22(6), 566-70, 1987.
- Peters, MA, Lau, EP, Snitman, DL, Van Wyk, JJ, Underwood, LE, Russell, WE, Svoboda, ME Expression of a biologically active analogue of somatomedin-C/insulin-like growth factor I. Gene, 35(1-2), 83-9, 1985.
- Russell, WE Growth hormone, somatomedins, and the liver. Semin Liver Dis, 5(1), 46-58, 1985.
- Russell WE, D'Ercole AJ, Underwood LE "Somatomedin C/Insulinlike growth factor-I during liver regeneration in the rat. Am J Physiol (Endocrinol Metab 11)." , 248E618-E623, 1985.
- Russell, WE, D'Ercole, AJ, Underwood, LE Somatomedin C/insulinlike growth factor I during liver regeneration in the rat. Am J Physiol, 248(5 Pt 1), E618-23, 1985.
- Russell, WE, McGowan, JA, Bucher, NL Biological properties of a hepatocyte growth factor from rat platelets. J Cell Physiol, 119(2), 193-7, 1984.
- McGowan, JA, Russell, WE, Bucher, NL Hepatocyte DNA replication: effect of nutrients and intermediary metabolites. Fed Proc, 43(1), 131-3, 1984.
- Russell, WE, Van Wyk, JJ, Pledger, WJ Inhibition of the mitogenic effects of plasma by a monoclonal antibody to somatomedin C. Proc Natl Acad Sci U S A, 81(8), 2389-92, 1984.
- Russell WE, Van Wyk JJ, Pledger WJ "Inhibition of the mitogenic effects of plasma by a monoclonal antibody to somatomedin-C." Proc Natl Acad Sci USA, 812389-2392, 1984.
- Russell, WE, McGowan, JA, Bucher, NL Partial characterization of a hepatocyte growth factor from rat platelets. J Cell Physiol, 119(2), 183-92, 1984.
- Van Wyk, JJ, Russell, WE, Li, CH Synthetic somatomedin C: comparison with natural hormone isolated from human plasma. Proc Natl Acad Sci U S A, 81(3), 740-2, 1984.
- Kingsnorth, AN, Russell, WE, McCann, PP, Diekema, KA, Malt, RA Effects of alpha-difluoromethylornithine and 5-fluorouracil on the proliferation of a human colon adenocarcinoma cell line. Cancer Res, 43(9), 4035-8, 1983.
- Russell, WE, Bucher, NL Vasopressin modulates liver regeneration in the Brattleboro rat. Am J Physiol, 245(2), G321-4, 1983.
- Russell WE, Bucher NLR "Vasopressin modulates liver regeneration in the Brattleboro rat." Am J Physiol (Gastrointest Liver Physiol 8), 245G321-G324, 1983.
- McFadden, D, Jeffress, LA, Russell, WE Individual differences in sensitivity to interaural differences in time and level. Percept Mot Skills, 37(3), 755-61, 1973.
- Russell, WE Insolubilization and activation of arterial actomyosin by bivalent cations. Eur J Biochem, 33(3), 459-66, 1973.