Our research program concerns both basic cell biology and disease-oriented investigations.
Dynamic Spatial Relations in Eukaryotic Cells
Restrictions of the distribution of organelles and macromolecules are central to cellular organization and viability. As an outgrowth of former studies of transport along the secretory path and export from the nucleus, we are presently investigating several issues in S. cerevisiae. These are
- The mechanisms of fusion of the nuclear envelope, both during zygote formation and during the mitotic cell cycle. Nuclear fusion seldom occurs, but these events presumably are related to nuclear envelope breakdown and reformation in higher eukaryotic cells.
- The progressive equilibration of organelles as haploid cells form zygotes, with emphasis on the delay of encounter between parental mitochondria. This delay likely accounts for the unexplained yet classic observation that aspects of mitochondrial inheritance in yeast - as in higher eukaryotes - are uniparental.
- Shortly before completion of the mitotic cell cycle, the maternal and bud cytoplasm lie on opposite sides of the bud neck that is at least partially occluded by the nucleus. This condition is stabilized upon imposition of the DNA damage or spindle checkpoints. Our goal is to characterize the cell biology of these arrests, to identify conditions that bypass them, and to understand the importance of the nucleolus as a regulator of progression.
- Classical experiments have been thought to document transfer of chromosomes between the nuclei in dikaryons. We are reinvestigating these reports with the intent of discovering a more plausible explanation.
Nuclear resolution at the end of the cell cycle in S. cerevisiae. Time-lapse of cells expressing GFP-tagged tubulin and a red marker of the ER and nuclear envelope. Note that the spindle breaks into two rectiliniear fragments (arrow) which quickly leads to "dimpling" of the extremities of the nuclear envelope (stars). Lacking tension, the envelope itself then become irregular (bracket) and finally undergoes fission (double arrows).
Development of Genetic Strategies to Combat Disease
The universe of proteins that contribute to the phenotype of the organism is highly complex. Nevertheless, it is possible to devise strategies that identify key, functionally significant, contributors.
We are actively interested in two such strategies:
- Both in genetically "simple" diseases such as Huntington's Disease and in diseases of more complex causation such as cancer, the central challenge is to identify one or more agents that can normalize cell phenotype. We therefore have developed a genetic selection that allows streamlined enrichment and identification of corrective cDNAs.
- The range of possible application of this strategy is extremely broad.
- In related studies we are characterizing the successive transcriptional programs that are induced when the mutant huntingtin protein is first expressed. This strategy is designed to identify early changes that lead to pathogenesis.
Studies of Huntington’s Disease
In principle, Huntington’s Disease should be much more amenable to investigation than neurodegenerative diseases that lack uniform genetic linkage. Nevertheless, effective therapies for this disease have not been developed.
We are actively involved in three related projects:
- Identification of novel post-translational modifications of the huntingtin protein.
- Investigation of the phenotypic consequences of expression of mutant huntingtin in yeast.
- Characterizing transcriptional changes that occur when the mutant huntingtin protein is first expressed.
Former Lab Members
Sy Fatemi, MD PhD, University of Minnesota
Thomas Hattier, PhD, Cellular Technology, Ltd.
Cleveland Tatsuhiko Kadowaki, PhD
Nagoya University (Japan)
Shuang Liang, PhD Guangzhou University (China)
Michal Lichtenstein, PhD, Hebrew University
Jayasri Nanduri, PhD, University of Chicago
Hito Ohno, PhD, Kyoto University (Japan)
Roger Schneiter, PhD, University of Fribourg (Switzerland)
David Singleton, PhD, University of Virginia
Neena Singh, MD PhD, Case Western Reserve University
Tao Tao, PhD, Xiamen University (China)
Ellen Tisdale, Wayne State University
Jerrold Turner, MD PhD, University of Chicago
Peter Wiest, MD, MetroHealth, Cleveland
Di Wu, PhD, Harvard Medical School
Cure Huntington's Disease Initiative
CWRU Cancer Center
Kadowaki T, Goldfarb D, Spitz LM, Tartakoff A, Ohno M (1993) Regulation of RNA processing and transport by a nuclear guanine nucleotide release protein and members of the Ras superfamily. EMBO J 12, 2929-2937.
Kadowaki T, Chen S, Hitomi M, Jacobs E, Kumagai C, Liang S, Schneiter R, Singleton D, Wisniewska J, Tartakoff AM (1994) Isolation and characterization of S. cerevisiae mRNA transport-defective (mtr) mutants. J Cell Biol 126, 649-659.
Liang S, Hitomi M, Tartakoff A (1995) Adenoviral E1B-55kDa protein inhibits yeast mRNA export. Proc Natl Acad Sci 92, 7372-7375.
Singh N, Liang L-N, Tykocinski M, Tartakoff A (1996) A novel class of cell surface glycolipids of mammalian cells. J Biol Chem 271, 12879-12884.
Liang S, Hitomi M, Hu Y-H, Liu Y, Tartakoff A (1996) A DEAD-box family protein is required for nucleocytoplasmic transport of yeast mRNA. Mol Cell Biol 16, 5139-5146.
Liu Y, Liang S, Tartakoff A (1996) Heat shock disassembles the nucleolus. EMBO J 15, 6750-6757.
Tseng S, Weaver P, Liu Y, Hitomi M, Tartakoff A, Chang T-H (1998) A cytosolic RNA helicase required for poly(A)+ RNA export. EMBO J 17, 2651-2662.
Liu Y, Guo W, Tartakoff P, Tartakoff A (1999) A Crm1p-independent path for export of the mRNA-binding protein, Mtr13p/Npl3p. Proc Natl Acad Sci USA 96, 6739-6744.
Nanduri J, Mitra S, Andrei C, Liu Y, Yu Y, Hitomi M, Tartakoff A (1999) Unexpected link between the secretory path and the nucleus. J Biol Chem 274, 33785-33789.
Tao T, Tartakoff A (2001) Nuclear relocation of normal Huntington. Traffic 2, 385-394.
Lichtenstein M, Guo W, Tartakoff A (2001) Control of nuclear export of hn RNPA1. Traffic 2, 261-267.
Nanduri J, Tartakoff A (2001) Perturbation of the nucleus: a novel Hoglp-independent, Pkclp-dependent consequence of hypertonic shock. Mol Cell Biol 12, 1835-1841.
Nanduri J, Tartakoff A (2001) The arrest of secretion response. Mol Cell 8, 281-289.
Morel-Huaux VM, Pypaert M, Wouters S, Tartakoff AM, Jurgen U, Gevaert K, Courtoy P (2002) The calcium-binding protein p54/NEFA is a novel luminal resident of medial Golgi cisternae that traffics independently of mannosidase II. Eur J Cell Biol 81, 87-100.
Tartakoff AM (2002) George Emil Palade, Charismatic Virtuoso. Nature Rev Mol Cell Biol 3, 871-876.
Tartakoff AM, Matera AG, Pimplikar S, Weimbs T (2004) Regulation of nuclear functions - Nucleocytoplasmic transport in context. Eur J Cell Biol 83, 185-192.
Gabel L, Won S, Kawai H, McKinney M, Tartakoff A, Fallon J (2004) Visual experience regulates transient expression and dendritic localization of Fragile X mental retardation protein. J Neurosci 24, 10579-10583.
Wu, D. Townsley, E. and Tartakoff, A. Covert Genetic Selections to Optimize Cellular Phenotypes. PLoS-ONE 2, e1200 (2007).
Hattier, T., Andrulis, E. and Tartakoff, A. Immobility, Inheritance and Plasticity of Shape of the Yeast Nucleus. BMC Cell Biology 8, 47 (2007).
Liang, J., Ke, G., You, W., Peng,Z., Lan, J., Kalesse, M., Tartakoff, A., Kaplan, F. and Tao T. Interaction between importin 13 and myopodin suggests a nuclear import pathway for myopodin. Molecular and Cellular Biochemistry 307, 93-100 (2008).
Quan Y, Ji ZL, Wang X, Tartakoff AM, Tao T. Evolutionary and transcriptional analysis of karyopherin beta superfamily protein. Mol Cell Proteomics. 7, 1254-1269 (2008).
Tartakoff, A. and Jaiswal, P. Nuclear Fusion and Genome Encounter During Yeast Zygote Formation. Mol. Biol. Cell 20, 2932-2942 (2009). Selected for special mention by the journal.
Lin, W., Ye, W., Cai, L., Meng, X., Ke, G., Huang, C., Peng, Z., Yu, Y., Golden, J., Tartakoff, A. and Tao, T. The roles of multiple importins for nuclear import of murine aristaless-related homeobox protein. J. Biol Chem. 284, 20428-20439 (2009).
Li, C., Yu, S., Nakamura, M., Yin, S., Xu, J., Petrolla, A., Singh, N., Tartakoff, A., Abbott, D., Xin, W. and Sy, M. Binding of pro-prion to FLNa disrupts cytoskeleton and correlates with poor prognosis in pancreatic cancer. J. Clin. Invest. 119, 2725-2736 (2009).
Tartakoff, A. and Tao, T. Comparative and Evolutionary Aspects of Macromolecular Translocation Across Membranes. Int. J. Biochem and Cell Biol. 42, 214-229 (2010).
Ye W, Lin W, Tartakoff AM, Tao T. Karyopherins in nuclear transport of homeodomain proteins during development. Biochim Biophys Acta. (2011) 1813, 1654-62.
Smith SB, Kiss DL, Turk E, Tartakoff AM, Andrulis ED. Pronounced and Extensive Microtubule Defects in a Saccharomyces cerevisiae DIS3 Mutant. Yeast. 28, 755-69 (2011).
Pantopoulos K, Porwal SK, Tartakoff A, Devireddy L. Mechanisms of Mammalian iron homeostasis. Biochemistry. (2012) 51, 5705-24.
Zapanta Rinonos, S. Jeremy Saks, Jonida Toska, Chun-Lun Ni and Alan Michael Tartakoff. Flow Cytometry-Based Purification of S. cerevisiae Zygotes. Journal of Visualized Experiments 2012 Sep 21;(67):e4197.
A. Tartakoff, I. Aylyarov and P. Jaiswal. Septin-Containing Barriers Control the Differential Inheritance of Cytoplasmic Elements. Cell Rep. 2013 Jan 31;3(1):223-36.
Roy, S., Bonfield, T., & Tartakoff, A. Non-Apoptotic Toxicity of Pseudomonas aeruginosa Toward Murine Cells. PLOS ONE 2013;8(1):e54245.
Zapanta Rinonos S, Rai U, Vereb S, Wolf, K, Yuen E, Lin, C. Tartakoff AM. The Sequential Logic of Polarity Determination During the Haploid-to-Diploid Transition in S. cerevisiae. Eukaryotic Cell, 2014 Aug 29. Selected for special mention by the journal.
Tartakoff, AM. and Wu, D. The Axis of Disease Progression. Cancer Informatics, Supplementary Issue: Network and Pathway Analysis of Cancer Susceptibility (B), Cancer Informatics 2014:13(S6), p.7-13.
Tartakoff AM. (2015) Cell biology of yeast zygotes, from genesis to budding. Biochim Biophys Acta. 1853(7):1702-14.