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A novel TEF factor cloned

Daniel Drolet

Appointment Period: 1993-1994 / Grant Year: [09]

During the period on this training grant I made considerable progress toward fulfilling our original goals. These goals included: (1) Completion of a functional gene targeting facility for the development of mouse lines with specific mutations in one or more developmentally important transcription factors. This goal has been achieved as we have successfully obtained germline transmission of two different ES cell clones each harboring a separate disruption of a transcription factor. The analysis of these mutant mice should help to determine the developmental role(s) of these transcription factors. (2) Completion of the characterization of the murine gene encoding thyrotroph embryonic factor (TEF), a PAR-bZIP transcription factor. (3) Determining the developmental ontogeny of expression of hepatic leukemia fac tor (HLF), a PAR-bZIP transcription factor. By in situ hybridization anal ysis we have already established that HLF, like TEF, is expressed in the rostral portion of the rodent anterior pituitary gland. Furthermore, we have identified several specific brain regions which express high levels of HLF mRNA. We have begun to examine the potential interaction of TEF and HLF in regard to their effect on transcription of pituitary target genes. This work will be continued in the laboratory.

PUBLICATIONS (resulting from this training, and some recent ones)

Lira SA, Kalla KA, Glass CK, Drolet DW, Rosenfeld MG. (1993) Synergistic interactions between Pit-1 and other elements are required for effective somatotroph rat growth hormone gene expression in transgenic mice. Mol Endocrinol. 7:694-701.

Wegner M, Drolet DW, Rosenfeld MG. (1993) POU-domain proteins: structure and function of developmental regulators. Curr Opin Cell Biol. 5:488-98.

Wegner M, Drolet DW, Rosenfeld MG. (1993) Regulation of JC virus by the POU-domain transcription factor Tst-1: implications for progressive multifocal leukoencephalopathy. Proc Natl Acad Sci USA 1993 90:4743-7.

Lin SC, Li S, Drolet DW, Rosenfeld MG. (1994) Pituitary ontogeny of the Snell dwarf mouse reveals Pit-1-independent and Pit-1-dependent origins of the thyrotrope. Development. 120:515-22.

Pearse RV 2nd, Drolet DW, Kalla KA, Hooshmand F, Bermingham JR Jr, Rosenfeld MG. (1997) Reduced fertility in mice deficient for the POU protein sperm-1. Proc Natl Acad Sci USA 94:7555-60.

Hitzler JK, Soares HD, Drolet DW, Inaba T, O'Connel S, MG Rosenfeld, Morgan JI, Look AT. (1999) Expression patterns of the hepatic leukemia factor gene in the nervous system of developing and adult mice. Brain Res. 820:1-11.

Bridonneau P, Bunch S, Tengler R, Hill K, Carter J, Pieken W, Tinnermeier D, Lehrman R, Drolet DW. (1999) Purification of a highly modified RNA-aptamer. Effect of complete denaturation during chromatography on product recovery and specific activity. J Chromatogr B Biomed Sci Appl. 726:237-47.

Romig TS, Bell C, Drolet DW. (1999) Aptamer affinity chromatography: combinatorial chemistry applied to protein purification. J Chromatogr B Biomed Sci Appl. 731:275-84.

Tucker CE, Chen LS, Judkins MB, Farmer JA, Gill SC, Drolet DW. (1999) Detection and plasma pharmacokinetics of an anti-vascular endothelial growth factor oligonucleotide-aptamer (NX1838) in rhesus monkeys. J Chromatogr B Biomed Sci Appl. 732:203-12.

Drolet DW, Jenison RD, Smith DE, Pratt D, Hicke BJ. (1999) A high throughput platform for systematic evolution of ligands by exponential enrichment (SELEX). Comb Chem High Throughput Screen. 2:271-8.

Drolet DW, Nelson J, Tucker CE, Zack PM, Nixon K, Bolin R, Judkins MB, Farmer JA, Wolf JL, Gill SC, Bendele RA. (2000) Pharmacokinetics and safety of an anti-vascular endothelial growth factor aptamer (NX1838) following injection into the vitreous humor of rhesus monkeys. Pharm Res. 17:1503-10.

Desjardins J, Emerson DL, Colagiovanni DB, Abbott E, Brown EN, Drolet DW. (2004) Pharmacokinetics, safety, and efficacy of a liposome encapsulated thymidylate synthase inhibitor, OSI-7904L [(S)-2-[5-[(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]amino-1-oxo-2-isoindolynl]-glutaric acid] in mice. J Pharmacol Exp Ther. 309:894-902.

Goss G, Siu LL, Gauthier I, Chen EX, Oza AM, Goel R, Maroun J, Powers J, Walsh W, Maclean M, Drolet DW, Rusk J, Seymour LK; Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group. (2006) A phase I, first in man study of OSI-7836 in patients with advanced refractory solid tumors: IND.147, a study of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group. Cancer Chemother Pharmacol. 58:703-10.

Colagiovanni DB, Drolet DW, Dihel L, Meyer DJ, Hart K, Wolf J. (2006) Safety assessment of 4'-thio-beta-D-arabinofuranosylcytosine in the beagle dog suggests a drug-induced centrally mediated effect on the hypothalamic-pituitary-adrenal axis. Int J Toxicol. 25:119-26.

Lee CP, de Jonge MJ, O'Donnell AE, Schothorst KL, Hanwell J, Chick JB, Brooimans RA, Adams LM, Drolet DW, de Bono JS, Kaye SB, Judson IR, Verweij J. (2006) A phase I study of a new nucleoside analogue, OSI-7836, using two administration schedules in patients with advanced solid malignancies. Clin Cancer Res. 12:2841-8.

Falk S, Anthoney A, Eatock M, Van Cutsem E, Chick J, Glen H, Valle JW, Drolet DW, Albert D, Ferry D, Ajani J. (2006) Multicentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma. Br J Cancer. 95:450-6.