Publications by authors named "Alicia Farmer"

3 Publications

  • Page 1 of 1

Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia.

Blood 2012 Nov 3;120(23):4621-34. Epub 2012 Oct 3.

Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.

The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of XPO1, thereby inhibiting nuclear export of cargo proteins. The clinical relevance of SINEs was explored in chronic lymphocytic leukemia (CLL), a disease associated with recurrent XPO1 mutations. Evidence is presented that SINEs can restore normal regulation to the majority of the dysregulated pathways in CLL both in vitro and in vivo and induce apoptosis of CLL cells with a favorable therapeutic index, with enhanced killing of genomically high-risk CLL cells that are typically unresponsive to traditional therapies. More importantly, SINE slows disease progression, and improves overall survival in the Eμ-TCL1-SCID mouse model of CLL with minimal weight loss or other toxicities. Together, these findings demonstrate that XPO1 is a valid target in CLL with minimal effects on normal cells and provide a basis for the development of SINEs in CLL and related hematologic malignancies.
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http://dx.doi.org/10.1182/blood-2012-05-429506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3512237PMC
November 2012

Sequence and structural analyses of nuclear export signals in the NESdb database.

Mol Biol Cell 2012 Sep 25;23(18):3677-93. Epub 2012 Jul 25.

Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.

We compiled >200 nuclear export signal (NES)-containing CRM1 cargoes in a database named NESdb. We analyzed the sequences and three-dimensional structures of natural, experimentally identified NESs and of false-positive NESs that were generated from the database in order to identify properties that might distinguish the two groups of sequences. Analyses of amino acid frequencies, sequence logos, and agreement with existing NES consensus sequences revealed strong preferences for the Φ1-X(3)-Φ2-X(2)-Φ3-X-Φ4 pattern and for negatively charged amino acids in the nonhydrophobic positions of experimentally identified NESs but not of false positives. Strong preferences against certain hydrophobic amino acids in the hydrophobic positions were also revealed. These findings led to a new and more precise NES consensus. More important, three-dimensional structures are now available for 68 NESs within 56 different cargo proteins. Analyses of these structures showed that experimentally identified NESs are more likely than the false positives to adopt α-helical conformations that transition to loops at their C-termini and more likely to be surface accessible within their protein domains or be present in disordered or unobserved parts of the structures. Such distinguishing features for real NESs might be useful in future NES prediction efforts. Finally, we also tested CRM1-binding of 40 NESs that were found in the 56 structures. We found that 16 of the NES peptides did not bind CRM1, hence illustrating how NESs are easily misidentified.
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http://dx.doi.org/10.1091/mbc.E12-01-0046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442415PMC
September 2012

Recognition of nuclear targeting signals by Karyopherin-β proteins.

Curr Opin Struct Biol 2010 Dec 13;20(6):782-90. Epub 2010 Oct 13.

Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9041, USA.

The Karyopherin-β family of nuclear transport factors mediates the majority of nucleocytoplasmic transport. Although each of the 19 Karyopherin-βs transports unique sets of cargos, only three classes of nuclear localization and export signals, or NLSs and NESs, have been characterized. The short basic classical-NLS was first discovered in the 1980s and their karyopherin-bound structures were first reported more than 10 years ago. More recently, structural and biophysical studies of Karyopherin-β2-cargo complexes led to definition of the complex and diverse PY-NLS. Structural knowledge of the leucine-rich NES is finally available more than 10 years after the discovery of its recognition by the exportin CRM1. We review recent findings relating to how these three classes of nuclear targeting signals are recognized by their Karyopherin-β nuclear transport factors.
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http://dx.doi.org/10.1016/j.sbi.2010.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994982PMC
December 2010