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Department
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Hematology/Oncology
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Hospital Title
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Chief Emeritus, Division of Oncology/Hematology
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Academic Title
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Robert A. Stranahan Professor of Pediatrics
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Phone
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617-919-2093
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Fax
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617-730-0469
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Email
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Samuel Lux
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Location
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300 Longwood Avenue
Karp 07006.E
Boston, MA 02115
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Samuel Lux's research has focused on anemias, particularly spherocytosis and other membrane disorders of red blood cells. For the three decades, work in his laboratory has focused on the organization and functions of the spectrin-based membrane skeleton. Current work is directed at two related problems:
- Spectrin function. Spectrin is the major protein of the membrane skeleton. Spectrins are composed of two long flexible chains (α and β) that bind side to side. Spectrins self-associate at one end, and bind to actin with the help of protein 4.1 at the other end. The Lux group is studying the spectrin-actin interaction because it is poorly understood. They have recently helped characterize the actin and protein 4.1 binding sites at the end of beta spectrin, in collaboration with a colleague, Mohandas Narla, and are now focusing on the neighboring portion of alpha spectrin, which was previously considered inert. They find this domain binds protein 4.2 in a Ca2+-dependent manner, and that the domain is necessary for actin binding. Three mouse mutations with defects in the domain have recently been discovered and have different and interesting phenotypes, which imply even more undiscovered functions. To identify these, they are preparing mini-spectrins from the expressed normal and mutant spectrin domains, and are analyzing their interactions with actin, 4.1, 4.2 and other neighboring membrane skeletal proteins.
- Hereditary spherocytosis. The Lux group and other researchers have shown that hereditary spherocytosis (HS) is caused by defects in the connections that attach the membrane skeleton to the overlying lipid bilayer. They have also identified beta spectrin as a probable modifier locus in mice. They are beginning to search for modifier loci in humans, using a candidate gene approach. They are also studying the consequences of splenectomy, particularly the possibility that splenectomy may predispose HS patients to thromboembolic disease and pulmonary hypertension.
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Samuel Lux received his MD in 1967 from Kansas University School of Medicine. He completed an internship and residency at Children's Hospital in Boston and fellowships in protein chemistry at the National Institutes of Health and in hematology/oncology at Children's. He also spent two years with Harvey Lodish at the Whitehead Institute in 1985-1987 studying molecular biology.
He is the recipient of numerous honors and awards for teaching and research, including the E. Mead Johnson Award from the Society for Pediatric Research and American Society of Hematology's prestigious Dameshek and E. Donnall Thomas Awards for pioneering research.
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- Eber SW, Gonzalez JM, Lux ML, Scarpa AL, Tse WT, Dornwell M, Herbers J, Kugler W, Ozcan R, Pekrun A, Gallagher PG, Schrter W, Forget BG, Lux SE. Ankyrin 1 mutations are a major cause of dominant and recessive spherocytosis. Nat Genet 1996; 13:214-18.
- Peters LL, Shivdasani RA, Liu S-C, Hanspal M, John KM, Gonzalez J, Brugnara C, Gwynn B, Mohandas N, Alper S, Orkin S, Lux SE. Anion exchanger 1 (Band 3) is required to prevent erythrocyte membrane surface loss but not to form the membrane skeleton. Cell 1996; 86: 917-927.
- Stankewich MC, Tse WT, Peters LL, Ch'ng Y, John, KM, Stabach PR, Devarajan, P, Morrow JS, Lux SE. A widely expressed _III spectrin associated with Golgi and cytoplasmic vesicles. Proc. Natl. Acad. Sci. USA 1998; 95: 14158-14163.
- Tse WT, Tang J, Jin O, Korsgren C, John KM, Kung AL, Gwynn B, Peters LL, Lux SE. A new spectrin, dIV, has a major truncated isoform that associates with promyelocytic leukemia protein nuclear bodies and the nuclear matrix. J Biol Chem 2001; 276:23974-23985.
- Paw BH, Davidson AJ, Zhou Y, Li R, Pratt SJ, Trede NS, Brownlie A, Donovan A, Liao EC, Ziai JM, Drejer A, Guo W, Kim CH, Gwynn B, Peters LL, Chernova MN, Alper S, Zapata A, Wickramasinghe SN, Lee MJ, Lux SE, Fritz A, Postlethwait JH, Zon LI. Cell-specific mitotic defect and dyserythropoiesis associated with erythroid band 3 deficiency. Nat Genet 2003; 34: 59-64.
- Peters LL. Swearingen RA. Andersen SG. Gwynn B. Lambert AJ. Li R. Lux SE. Churchill GA. Identification of quantitative trait loci that modify the severity of hereditary spherocytosis in wan, a new mouse model of band-3 deficiency. Blood 2004; 103:3233-40.
- An X, Debnath G, Guo X, Liu S, Lux SE, Baines A, Gratzer W, Mohandas N. Identification and functional characterization of protein 4.1R and actin-binding sites in erythrocyte beta spectrin: regulation of the interactions by phosphatidylinositol-4,5-bisphosphate. Biochemistry 2005; 44:10681-8.
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