Theodore L. Steck, MD

Professor Emeritus, Biochemistry and Molecular Biology, Molecular Genetics and Cell Biology

B.S., Lawrence College, 1960
M.D., Harvard Medical School, 1964

Research Summary

My long-term research interest is in membrane biochemistry. Over the years, I have studied the molecular organization of the human red cell membrane and several aspects of the cell biology of the ameba, Dictyostelium discoideum. In addition, the disposition of cell cholesterol has been a recurrent focus. We are currently investigating cellular cholesterol homeostasis: how cells sense their need for this essential plasma membrane lipid and make appropriate adjustments to keep it in balance. We suggest that cells gauge the magnitude of the bulk pool of cholesterol in the plasma membrane by sensing the high activity of the cholesterol in excess of phospholipids. This active excess sets the size of the sterol pool in the endoplasmic reticulum and mitochondria through the flow of cholesterol between the cell surface and intracellular membranes. The endoplasmic reticulum pool then sets the level of activity of several regulatory elements in its membrane that mediate sterol homeostasis while the mitochondria convert cholesterol to oxysterols that serve as messengers of cholesterol excess. The elements of this cholesterol sensing system and how it can be manipulated are under investigation.

Selected Publications

Lange, Y. and Steck, T.L. (2016). Active membrane cholesterol as a physiological effector. Chem Phys Lipids. pii: S0009-3084(16)30015-9. doi: 10.1016/j.chemphyslip.2016.02.003. (PubMed)

Czyz DM, Potluri LP, Jain-Gupta N, Riley SP, Martinez JJ, Steck TL, Crosson S, Shuman HA, Gabay JE. Host-directed antimicrobial drugs with broad-spectrum efficacy against intracellular bacterial pathogens. MBio. 2014; 5(4):e01534-14. (PubMed)

Lange Y, Ye J, Steck TL. Essentially all excess fibroblast cholesterol moves from plasma membranes to intracellular compartments. PLoS One. 2014; 9(7):e98482. (PubMed)

Tietjen GT, Gong Z, Chen CH, Vargas E, Crooks JE, Cao KD, Heffern CT, Henderson JM, Meron M, Lin B, Roux B, Schlossman ML, Steck TL, Lee KY, Adams EJ. Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4. Proc Natl Acad Sci U S A. 2014 Apr 15; 111(15):E1463-72. (PubMed)

Lange Y, Tabei SM, Ye J, Steck TL. Stability and stoichiometry of bilayer phospholipid-cholesterol complexes: relationship to cellular sterol distribution and homeostasis. Biochemistry. 2013 Oct 8; 52(40):6950-9. (PubMed)

Lange, Y., Ye, J., and Steck, T.L. (2012) Activation mobilizes the cholesterol in the late endosomes-lysosomes of Niemann Pick Type C cells. PLoS One 7, e30051. (PubMed)

Steck, T.L., and Lange, Y. (2010) Cell cholesterol homeostasis: Mediation by active cholesterol. Trends in Cell Biology 20, 680-687. (PubMed)

Lange, Y., Ye, J., Duban, M.-E., and Steck, T. L. (2009) Activation of Membrane Cholesterol by 63 Amphipaths. Biochemistry 48, 8505-8515. (PubMed)

Lange, Y., Steck, T. L., Ye, J., Lanier, M. H., Molugu, V., and Ory, D. (2009) Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol. Journal of Lipid Research 50, 1881-1888. (PubMed)

Lange, Y., and Steck, T.L. (2008). Cholesterol homeostasis and the escape tendency (activity) of plasma membrane cholesterol. Prog Lipid Res 47, 319-332. (PubMed)

Lange, Y., Ory, D.S., Ye, J., Lanier, M.H., Hsu, F.-F., and Steck, T.L. (2008). Effectors of Rapid Homeostatic Responses of Endoplasmic Reticulum Cholesterol and 3-Hydroxy-3-methylglutaryl-CoA Reductase. J Biol Chem 283, 1445-1455. (PubMed)

Ratajczak, M.K., Ko, Y.T.C., Lange, Y., Steck, T.L., and Lee, K.Y.C. (2007). Cholesterol Displacement from Membrane Phospholipids by Hexadecanol. Biophys J 93, 2038-2047. (PubMed)

Lange Y, Ye J, Steck TL. (2007). Scrambling of phospholipids activates red cell membrane cholesterol. Biochemistry. 46(8):2233-8. (PubMed)

Terence E. Martin, PhD

Professor Emeritus, Molecular Genetics and Cell Biology
Committee on Immunology

B.S., Biochemistry, University of Adelaide, 1961
Ph.D., Biochemistry, University of Cambridge, 1966

Research Summary

Current research continues to be centered on basic mechanisms of gene expression, particularly in regard to nuclear structure and RNA synthesis and processing; in this regard we have studied the influence of viruses on the nuclear protein antigens of autoimmune disease. The reorganization of these nuclear antigens during normal development and during apoptosis has also been addressed in collaboration with several European laboratories. Currently the proteins directly involved in RNA transcription elongation are under study, and this has led to an active collaboration on the relationship of transcription to somatic hypermutation of Ig genes with Ursula Storb (see recent publications).

Our recent discovery of a novel stomach protein, expressed only in the lumenal surface epithelial cells, has led us to initiate a study of this gene in humans and mice. We have raised high-titer antibodies to the protein and used immuno-electron microscopy to localize it to secretion granules of mucosal epithelial cells. Our current studies have demonstrated that it has growth factor activity; the additional possibility that it can serve as a precursor of bioactive peptides with a role in innate immunity in the stomach is being explored. Given the need for rapid replacement of gastric epithelial cells as a result of the acid environment, mechanical damage and possible bacterial infiltration it is likely that this factor is important in the maintenance and restitution of the stomach epithelium. We propose to analyze the mechanism of gastric epithelial cell growth stimulation and study the consequences of a knockout of this gene in mice.

Selected Publications

Toback, F. G., Walsh-Reitz, M. M., Musch, M. W., Chang, E. B., Del Valle, J., Ren, H., Huang, E. and Martin, T. E. (2003). "Peptide fragments of AMP-18, a novel secreted gastric antrum mucosal protein, are mitogenic and motogenic." Am J Physiol Gastrointest Liver Physiol 285: G344-53. (PubMed)

Vazquez-Nin, G. H., Echeverria, O. M., Ortiz, R., Scassellati, C., Martin, T. E., Ubaldo, E. and Fakan, S. (2003). "Fine Structural Cytochemical Analysis of Homologous Chromosome Recognition, Alignment, and Pairing in Guinea Pig Spermatogonia and Spermatocytes." Biol Reprod. (PubMed)

Kim, N., Martin, T. E., Simon, M. C. and Storb, U. (2003). "The transcription factor Spi-B is not required for somatic hypermutation." Mol Immunol 39: 577-83. (PubMed)

Martin, T. E., Powell, C. T., Wang, Z., Bhattacharyya, S., Walsh-Reitz, M. M., Agarwal, K. andToback, F. G. (2003). "A novel mitogenic protein that is highly expressed in cells of the gastric antrum mucosa." Am J Physiol Gastrointest Liver Physiol 285: G332-43. (PubMed)

Michael, N., Martin, T. E., Nicolae, D., Kim, N., Padjen, K., Zhan, P., Nguyen, H., Pinkert, C. and Storb, U. (2002). "Effects of sequence and structure on the hypermutability of immunoglobulin genes." Immunity 16: 123-34. (PubMed)

Soldani, C., Bottone, M. G., Biggiogera, M., Alpini, C., Scovassi, A. I., Martin, T. and Pellicciari, C. (2002). "Nuclear localization of phosphorylated c-Myc protein in human tumor cells." Eur J Histochem 46: 377-80. (PubMed)

Pellicciari, C., Bottone, M. G., Scovassi, A. I., Martin, T. E. and Biggiogera, M. (2000). "Rearrangement of nuclear ribonucleoproteins and extrusion of nucleolus-like bodies during apoptosis induced by hypertonic stress." Eur J Histochem 44: 247-54. (PubMed)

Anthony P. Mahowald, PhD

Louis Block Professor Emeritus, Molecular Genetics and Cell Biology
Committee on Developmental Biology, Committee on Genetics

B.S., Biology, Spring Hill College, 1958
Ph.D., Biology, Johns Hopkins University, 1962

Research Summary

My laboratory is investigating the genetic control of key developmental events, using Drosophila melanogaster as our organism. Our approach has been to identify genetically as many of the components of the process as possible, attempt to order these elements through genetic interactions, and then move to a molecular analysis of the central genes in the process. Since becoming Emeritus, I have concentrated on a set of mutations that affect the mitochondrial derivative during spermiogenesis. In wild-type flies all the mitochondria in each spermatid fuse into two mitochondria which interweave with each other in the Nebenkern. During growth of the axoneme the two mitochondria unwind from each other and extend along the growing axoneme. Mutations which interfere with either the fusion process or the extension process are sterile. Efforts are in progress to identify the molecular processes involved in more than 25 different mutations affecting these events. I also continue a collaboration with Dr. Yuzo Niki in Japan to develop protocols for the culture of ovarian germline stem cells. We have shown that cultured cells can repopulate the germline and produce functional eggs. We currently have stable cultures composed of mixed populations of somatic and germline cells. If gene replacement methods can be developed for germline cells in these cultures, these cells could be the source for genetically modified germlines in flies.

Selected Publications

Srinivasan, S., Mahowald, A. P. and Fuller, M. T. 2012. The receptor phosphatase Lar regulates adhesion between Drosophila male germline stem cells and the niche. Development 139: 1381-1390. (PubMed)

Lu, W., Casanueva, M. O., Mahowald, A. P., Kato, M., Lauterbach, D., and Ferguson, E. L. 2012. Niche-associated acgivation of rac promotes the asymmetric division of Drosophila female germline stem cells. PLoS Biol. 10: e1001357. (PubMed)

Chatterjuee, N., Rollins, J., Mahowald, A. P., and Bazinet, C. 2011. Neurotransmitter Transporter-Like: a male germline-specific SLC6 transporter required for Drosophila spermiogenesis. PLoS ONE 6: e16275. (PubMed)

Yamashita, Y. M., Mahowald, A. P., Perlin, J. R., and Fuller, M. T. 2007. Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science 315:518-21. (PubMed)

Niki, Y., Yamaguchi, T., and Mahowald, A. P. 2006. Establishment of stable cell lines of Drosophila germline stem cells. Proc. Natl. Acad. Sci. USA 103: 16325-16330. (PubMed)

Tazuke, S. I., C. Schulz, L. Gilboa, A. P. Mahowald, A. Guichet, A. Ephrussi, C. G. Wood, R. Lehmann and M. T. Fuller. 2002. A germ line specfic gap junction protein is required for survival of differentiating early germ cells. Development 129: 2529-2539.(PubMed)

Niki, Y. and Mahowald, A. P. (2003). "Ovarian cystocytes can repopulate the embryonic germ line and produce functional gametes." Proc Natl Acad Sci U S A 100: 14042-5. (PubMed)

Mahowald, A. P. (2001). "Assembly of the Drosophila germ plasm." Int Rev Cytol 203: 187-213. (PubMed)

Robert Haselkorn, PhD

Professor Emeritus, Molecular Genetics & Cell Biology, Biochemistry & Molecular Biology, Chemistry
Fanny L. Pritzker Distinguished Service Professor
Committee on Microbiology, Committee on Developmental Biology, Committee on Genetics

Research Summary

Our current program is focused on two sets of problems: heterocyst differentiation in filamentous cyanobacteria and the properties of the enzyme acetyl-CoA carboxylase (ACC).

The cyanobacterium Anabaena grows in very long chains, the cells carrying out green plant photosynthesis. When faced with a shortage of fixed nitrogen, specialized cells called heterocysts differentiate at regular intervals along each filament, usually separated by about ten vegetative cells. The heterocysts do not divide. They quit doing carbon fixation but instead create an anaerobic environment for nitrogen fixation. The sequenced genome of Anabaena contains about 7000 genes, of which about 1500 are expressed differentially during heterocyst development. This program involves a cascade of transcription that involves at the start a factor called HetR, which we discovered long ago. This protein is studied now by many labs. One of my alumni identified the palindromic sequence in the genome to which it binds and another found a small peptide that prevents that binding. We have crystallized HetR from many species of cyanobacteria and solved the X-ray structure of one from the thermophile Fischerella. We have also solved the structure of complexes of the HetR dimer with several palindromic DNA sequences, ones containing 21, 23 and 25 base pairs. This work is continuing, in collaboration with Andrzej Joachimiak at the Argonne National Laboratory, Michelle Ye in China, and Sean Callahan in Hawaii. We also follow single heterocyst differentiation using confocal fluorescence microscopy. The current program is pursued by postdocs Shan Ke and Amin Nasser.

The program on ACC is directed by Research Associate Piotr Gornicki, who was the first to purify the two wheat isozymes (chloroplast and cytoplasmic) and to clone their genes. We used their respective cDNAs in recombinant yeast to study the basis of herbicide sensitivity and found a single amino acid responsible for the resistance phenotype. The recombinant yeast system was then exploited to study the ACCs of parasites and eventually the two isoforms of human ACC. Currently, the lab is working on the human enzymes to determine possible targets for drugs to treat obesity.

Selected Publications

Youngchang Kim, Grazyna Joachimiak, Zi Ye, T. Andrew Binkowski, Rongguang Zhang, Piotr Gornicki, Sean M. Callahan, Wolfgang R. Hess, Robert Haselkorn and Andrzej Joachimiak. Structure of the Transcription Factor HetR Required for Heterocyst Differentiation in Cyanobacteria. Proc. Natl Acad. Sci USA 108: 10109-10114 (2011). (PubMed)

J. Marjanovic, D. Chalupska, C. Patenode, A. Coster, E. Arnold, A. Ye, G. Anesi, R.Y.Lu, I. Okun, S. Tkachenko, R. Haselkorn and P. Gornicki. A recombinant yeast screen for new inhibitors of human ACC2 identifies potential drugs to treat obesity. Proc. Nat. Acad. Sci. USA 107: 9093-9098 (2010). (PubMed)

Liu, W., Harrison, D.K., Chalupska, D., Gornicki, P., O’Donnell, C.C., Adkins, S.W., Haselkorn, R. and Williams, R.R. Single-site mutations in the carboxyltransferase domain of plastid acetyl-CoA carboxylase confer resistance to grass-specific herbicides. Proc. Natl Acad Sci. USA 104: 3627-3632 (2007). (PubMed)

Rouhaiainen,L., Vakkilainen, T., Siemer, B.L., Buikema, W., Haselkorn, R., and Sivonen, K. Genes coding for the synthesis of hepatotoxic heptapeptides (Microcystins) in the cyanobacterium Anabaena strain 90. App. Env. Micro. 70: 686-692 (2004). (PubMed)

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Ilaria Rebay, PhD

Professor, Ben May Department for Cancer Research
Committee on Cancer Biology; Committee on Development, Regeneration & Stem Cell Biology
Committee on Genetics, Genomics & Systems Biology; Committee on Cell & Molecular Biology

Douglas Bishop, PhD

Professor, Department of Radiation and Cellular Oncology
Committee on Cancer Biology
Committee on Genetics, Genomics & Systems Biology
Molecular Genetics and Cell Biology

Research Summary

Homologous recombination of DNA repairs DNA damage and also creates the physical connections between chromosomes needed for reductional chromosome segregation during meiosis. We study two recombination proteins, Dmc1 and Rad51 that are related to the bacterial repair protein, RecA. The mechanisms of recombinational repair of damage induced double strand breaks in DNA (DSBs) and the mechanism of meiotic recombination are very closely related in terms of the DNA intermediates that form; DSBs are normal intermediates in most or all meiotic recombination.

There are, however critical differences in how meiotic recombination is regulated as compared to mitotic recombinational repair. Our research is directed at understanding how Dmc1's function is specialized for meiosis, how the functions of Rad51 and Dmc1 differ, how the two proteins interact with one another during meiosis, and how the two proteins interact with components of the synaptonemal complex. Our studies have shown that while the functions of Rad51 and Dmc1 overlap, they are also functionally distinct.

Using biochemical techniques we recently showed that, like yeast Rad51 protein, yeast Dmc1 protein promotes strand exchange. These results open the door to future efforts to reconstitute regulated homologous recombination reactions in vitro. We were first to show that recombination proteins can be detected at multiple subnuclear sites during recombination using immunostaining techniques. We have used this method to identify proteins required for recruitment of recombinase to double strand break sites in mitotic and meiotic cells. Among such regulators is the breast cancer susceptibility gene BRCA1. We have shown that BRCA1 promotes recombinase assembly and we are currently working to determine the mechanism through which BRCA1 mediates this effect.

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