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Thesis advisor: Junona Moroianu / The E7 protein of low risk HPV11 has been shown to interact with multiple proteins, including pRb, in both the cytoplasm and the nucleus. High risk HPV16 E7 and low risk HPV11 E7 share a novel nuclear import pathway independent of karyopherins but dependent on the GTPase Ran (Angeline, et al., 2003; Knapp, et al., 2009; Piccioli, et al., 2010). We continued to analyze the nucleocytoplasmic transport of HPV11 E7 in vivo through transfection assays in HeLa cells with EGFP-HPV11 E7 wild type and mutant fusion constructs. We found that nuclear localization of HPV11 E7 is mediated by a nuclear localization signal located in the C-terminal domain which contains a unique zinc-binding domain. Mutations of cysteine residues that interfered with zinc-binding clearly disrupted the nuclear localization of the EGFP-11cE7 and EGFP-11E7 mutants. These data suggest that the integrity of the zinc-binding domain is essential for the nuclear localization of HPV11 E7. In addition, we discovered that HPV11 E7 has a leucine-rich C-terminal nuclear export signal (NES) (76IRQLQDLLL84) mediating the nuclear export of HPV11 E7 in a CRM1-dependent manner. / Thesis (BS) — Boston College, 2011. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Biology Honors Program. / Discipline: Biology.

Histone Deacetylase (HDAC) plays a vital role in cellular processes, for example gene expression, cell growth, and apoptosis. Finding drug candidates to inhibit the over activity of HDACs in cancer is a growing area of interest. Inhibitors, thus far, have three important motifs to be studied: the zinc binding group, a hydrophobic linker, and a cap group. By altering these groups on the inhibitor, not only can activity be increased but also selectivity within the classes of HDACs. We present the design of two novel sets of molecules that contain either a 1,2,3-triazole or 1,2,4-triazole. The 1,2,3-triazoles were synthesized using “click chemistry” with a novel pyridyl triazine catalyst. The 1,2,4-triazoles were synthesized utilizing substitution chemistry. This set of molecules was designed after suberoylanilide hydroxamic acid (SAHA) but replaced the hydroxamate with the triazole as the zinc binding group. The activity of these inhibitors against HDAC 1, HDAC 6, and SIRT 1 were tested using the Biomol Fluor de Lys in vitro kits. Though none of the synthesized compounds were strong activators or inhibitors of any of the classes of HDACs, trends were observed that could lead to the design of more potent inhibitors.

Histone Deacetylase (HDAC) plays a vital role in cellular processes, for example gene expression, cell growth, and apoptosis. Finding drug candidates to inhibit the over activity of HDACs in cancer is a growing area of interest. Inhibitors, thus far, have three important motifs to be studied: the zinc binding group, a hydrophobic linker, and a cap group. By altering these groups on the inhibitor, not only can activity be increased but also selectivity within the classes of HDACs. We present the design of two novel sets of molecules that contain either a 1,2,3-triazole or 1,2,4-triazole. The 1,2,3-triazoles were synthesized using “click chemistry” with a novel pyridyl triazine catalyst. The 1,2,4-triazoles were synthesized utilizing substitution chemistry. This set of molecules was designed after suberoylanilide hydroxamic acid (SAHA) but replaced the hydroxamate with the triazole as the zinc binding group. The activity of these inhibitors against HDAC 1, HDAC 6, and SIRT 1 were tested using the Biomol Fluor de Lys in vitro kits. Though none of the synthesized compounds were strong activators or inhibitors of any of the classes of HDACs, trends were observed that could lead to the design of more potent inhibitors.

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京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第18316号 / 農博第2041号 / 新制||農||1020(附属図書館) / 学位論文||H26||N4823(農学部図書室) / 31174 / 京都大学大学院農学研究科食品生物科学専攻 / (主査)教授 保川 清, 教授 安達 修二, 教授 伏木 亨 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

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