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Scientific Accomplishments

Paul Lambert, PhD – Human Cancer Virology Program

Dr. Lambert’s laboratory studies the roles of the human papillomavirus oncogenes in cervical cancer. Analysis of the Bi-L E7 transgenic mice, generated by Transgenic and Mutant Animal Facility (TAF), showed for the first time that persistence of cervical lesions in vivo requires continuous expression of E7. Thus, anti-HPV therapy targeting E7 may be an effective strategy for the treatment of cervical cancer.

Jabbar SF, Abrams L, Glick A and Lambert PF.Persistence of high-grade cervical dysplasia and cervical cancer requires the continuous expression of the human papillomavirus type 16 E7 oncogene. Cancer Res. 2009, 69(10):4407-4414. (NIH grants CA022443, CA098428)

 

Sections of endocervices from bi-transgenic mice expressing E7 for the indicated time. A. Composite images (10X mag., insets 40X) of H&E stained  sections showing cancers in mice receiving no doxycycline (left) or 3d (middle) or 1mo (right) of doxycycline. B. H&E stained sections (40X mag.) of the endocervical epithelium showing high grade dysplasia in a bi-transgenic mouse receiving no doxycycline(left) and the regression of the lesion on treatment with doxycycline for 3d (middle) or 1mo (right). C and D. Immunohistochemical analysis for BrdU (C) and MCM7 (D) in the endocervical epithelium of mice receiving no doxycycline (left), 3d of doxycycline (middle) or 1mo of doxycycline (right). Black line, basement membrane. Insets, tumors from the same mice. Histology services provided by University of Wisconsin Carbone Cancer Center (UWCCC) Experimental Pathology Shared Resource.

 

Shigeki Miyamoto, PhD – Cell Signaling Program

Nuclear factor-kappa B (NF-κB) signaling plays a critical role in carcinogenesis. TAF generated knockout mice carrying a germline mutation in the nuclear export signal (NES) of the NF-κB inhibitor, IκBα. Analysis of these mutant mice allowed investigators to discover a novel, critical in vivo role for the NES. Further studies using this model will have a major impact on identifying targets for new chemopreventive/therapeutic approaches for many different human cancers.

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Wuerzberger-Davis SM, Chen Y, Yang DT, Kearns JD, Bates PW,  Lynch C, Ladell NC, Yu M, Podd A, Zeng H, Huang TT, Wen R, Hoffmann A, Wang D, and Miyamoto S. Nuclear export of the NF-κB inhibitor IκBα is required for proper B cell and secondary lymphoid tissue formation. Immunity 2011;34(2):188-200.(NIH grants CA081065, CA077474, GM083681)

 

IκBα NES mutant mice are defective in formation of secondary lymphoid organs, B cell maturation and antibody production. Inguinal lymph nodes were often bilaterally absent in mutant mice (A) or showed disrupted B cell organization (B) and were considerably smaller (C). The number of mature B cells was reduced in spleen (D). Additionally, serum IgA, IgG1 and IgG2b were reduced in mutant mice (E). Histology and flow cytometry services provided by UWCCC Experimental Pathology and Flow Cytometry Shared Resources.

 

Emery Bresnick, PhD – Cancer Genetics Program
Dr. Bresnick’s laboratory studies the role of the Gata2 transcription factor, which is found mutated acute myeloid leukemia, in development and disease. TAF generated transgenic mice in which lacZ expression is driven by different Gata2 enhancer elements. Analysis of these mice identified an enhancer active in both endothelial and hematopoietic cells and an enhancer preferentially required in endothelial cells. This study provides a strong foundation for further studies on the role of Gata2 in hematopoietic cancers.

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Wozniak RJ, Boyer ME, Grass JA, Lee Y and Bresnick EH. Context-dependent GATA factor function: combinatorial requirements for transcriptional control in hematopoietic and endothelial cells. J Biol Chem. 2007;282:14665-14674. (NIH grant DK68634)

 

Endothelial enhancer activity of Gata2 +9. 5 site in vivo. A. Whole mount and transverse sections of E11 transgenic embryos expressing LacZ (blue cells) under control of the Gata2+9.5 site fused to the Gata21S promoter. LacZ staining (arrowheads) was observed in DA, dorsal aorta; EC, endocardium;FL, fetal liver. B. Whole mount and transverse sections of E11 transgenic embryos containing the Gata2-3.9 site fused to the Gata21S promoter. Endothelial and hematopoietic (FL) staining was absent in (-3.9) 1SLacZ transgenic embryos. C. Enhancer activities of Gata2 switch site regions (-3.9, -1.8, and +9.5) in human endothelial cells. HUVECs and HAECs were transiently transfected with reporter plasmids in which the Gata21S promoter was cloned upstream of luciferase (1SLuc). Shown are the luciferase activities of the cell lysates. The activity of the 1SLuc construct was designated 1.0 (means+/-S.E.).