Henderson, M. C., Shaw, Y. Y., Wang, H., Han, H., Hurley, L. H., Flynn, G., Dorr, R. T., & D., D. (2009). UA62784, a novel inhibitor of centromere protein E kinesin-like protein. Molecular Cancer Therapeutics, 8(1), 36-44.
PMID: 19139111;PMCID: PMC2634858;Abstract:
Pancreatic carcinoma is the fourth leading cause of death from cancer. Novel targets and therapeutic options are needed to aid in the treatment of pancreatic cancer. The compound UA62784 is a novel fluorenone with inhibitory activity against the centromere protein E (CENP-E) kinesin-like protein. UA62784 was isolated due to its selectivity in isogenic pancreatic carcinoma cell lines with a deletion of the DPC4 gene. UA62784 causes mitotic arrest by inhibiting chromosome congression at the metaphase plate likely through inhibition of the microtubule-associated ATPase activity of CENP-E. Furthermore, CENP-E binding to kinetochores duringmitosis is not affected by UA62784, suggesting that the target lies within the motor domain of CENP-E. UA62784 is a novel specific inhibitor of CENP-E and its activity suggests a potential role for antimitotic drugs in treating pancreatic carcinomas. Copyright © 2009 American Association for Cancer Research.
Qin, Y., Rezler, E. M., Gokhale, V., Sun, D., & Hurley, L. H. (2007). Characterization of the G-quadruplexes in the duplex nuclease hypersensitive element of the PDGF-A promoter and modulation of PDGF-A promoter activity by TMPyP4. Nucleic Acids Research, 35(22), 7698-7713.
PMID: 17984069;PMCID: PMC2190695;Abstract:
The proximal 5′-flanking region of the human platelet-derived growth factor A (PDGF-A) promoter contains one nuclease hypersensitive element (NHE) that is critical for PDGF-A gene transcription. On the basis of circular dichroism (CD) and electrophoretic mobility shift assay (EMSA), we have shown that the guanine-rich (G-rich) strand of the DNA in this region can form stable intramolecular parallel G-quadruplexes under physiological conditions. A Taq polymerase stop assay has shown that the G-rich strand of the NHE can form two major G-quadruplex structures, which are in dynamic equilibrium and differentially stabilized by three G-quadruplex-interactive drugs. One major parallel G-quadruplex structure of the G-rich strand DNA of NHE was identified by CD and dimethyl sulfate (DMS) footprinting. Surprisingly, CD spectroscopy shows a stable parallel G-quadruplex structure formed within the duplex DNA of the NHE at temperatures up to 100 °. This structure has been characterized by DMS footprinting in the double-stranded DNA of the NHE. In transfection experiments, 10 μ M TMPyP4 reduced the activity of the basal promoter of PDGF-A ∼ 40%, relative to the control. On the basis of these results, we have established that ligand-mediated stabilization of G-quadruplex structures within the PDGF-A NHE can silence PDGF-A expression. © 2007 The Author(s).
II, B. M., Seaman, F. C., Wheelhouse, R. T., & Hurley, L. H. (1998). Mechanism for the catalytic activation of ecteinascidin 743 and its subsequent alkylation of guanine N2. Journal of the American Chemical Society, 120(10), 2490-2491.
Hannan, M. A., Estes, R., & Hurley, L. H. (1980). Induction and potentiation of lethal and genetic effects of ultraviolet light by tobacco smoke condensates in yeast. Environmental Research, 21(1), 97-107.
PMID: 6993205;Abstract:
Tobacco smoke condensates (TSC) were tested for DNA repair inhibition in both repair proficient and different classes of repair deficient strains of Saccharomyces cerevisiae. TSC was also tested for induction and potentiation of mutations and mitotic gene conversion in unirradiated and uv-irradiated yeast cells. TSC was found to sensitize all the strains of yeast to uv-inactivation indicating that it acts in a nonspecific manner and does not specifically inhibit a particular repair pathway. Genetic studies showed that TSC, without exogenous metabolic activation, failed to produce mutations while it induced mitotic gene conversion in the diploid strain. At specific concentrations, TSC potentiated both mutagenic and gene convertogenic effects uv-light while at higher concentrations of TSC a reduction of mutations was observed. The results are discussed as they relate to carcinogenesis and cocarcinogenesis/tumor promotion. © 1980.
González, V., Guo, K., Hurley, L., & Sun, D. (2009). Identification and characterization of nucleolin as a c-myc G-quadruplex-binding protein. Journal of Biological Chemistry, 284(35), 23622-23635.
PMID: 19581307;PMCID: PMC2749137;Abstract:
myc is a proto-oncogene that plays an important role in the promotion of cellular growth and proliferation. Understanding the regulation of c-myc is important in cancer biology, as it is overexpressed in a wide variety of human cancers, including most gynecological, breast, and colon cancers. We previously demonstrated that a guanine-rich region upstream of the P1 promoter of c-myc that controls 85-90% of the transcriptional activation of this gene can form an intramolecular G-quadruplex (G4) that functions as a transcriptional repressor element. In this study, we used an affinity column to purify proteins that selectively bind to the human c-myc G-quadruplex. We found that nucleolin, a multifunctional phosphoprotein, binds in vitro to the c-myc G-quadruplex structure with high affinity and selectivity when compared with other known quadruplex structures. In addition, we demonstrate that upon binding, nucleolin facilitates the formation and increases the stability of the c-myc G-quadruplex structure. Furthermore, we provide evidence that nucleolin overexpression reduces the activity of a c-myc promoter in plasmid presumably by inducing and stabilizing the formation of the c-myc G-quadruplex. Finally, we show that nucleolin binds to the c-myc promoter in HeLa cells, which indicates that this interaction occurs in vivo. In summary, nucleolin may induce c-myc G4 formation in vivo. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
