Regeneration and Cancer

Pamela L. Crowell, PhD
Brittney-Shea Herbert, Ph.D.

Pamela L. Crowell, PhD

Positions

• Associate Professor of Biology
• Associate Dean for Research and Graduate Education, School of Science

Address
Department of Biology
School of Science
Indiana University-Purdue University Indianapolis
723 W. Michigan St.
Indianapolis, IN 46202

Phone: (317) 278-1144
Fax: (317) 274-2846
Email: pcrowel@iupui.edu

Research Interests

The major research interests of my laboratory are in signal transduction and pancreatic cancer. We investigate the expression and function of the PRL-1, PRL-2, and PRL-3 tyrosine phosphatases in pancreatic and other cancers. PRL (PTPCAAX) phosphatases play a role in tissue development, differentiation, and proliferation. PRL-1 and PRL-2 are overexpressed at the mRNA and protein levels in approximately 40% of pancreatic and other solid cancers, and high PRL expression in pancreatic epithelial cells increases the rate of cell proliferation. Conversely, inhibition of PRL expression by siRNA causes a decrease in tumor cell proliferation, and thus PRL phosphatases represent novel molecular targets for the therapy of many human cancers. Little is currently known about PRL phosphatase signaling, and we are utilizing proteomic and bioinformatic approaches to elucidate these pathways in normal and cancerous tissues.

Recent Publications

• Cates, C. A., Michael, R. L., Stayrook, K. R., Harvey, K. A., Burke, Y. D., Randall, S. K., Crowell, P. L., and Crowell, D. N. (1996) Prenylation of oncogenic human PTPCAAX protein tyrosine phosphatases. Cancer Lett. 110: 49-55.
• Werner, S.R., Lee, P. A., DeCamp, M. W., Crowell, D. N., Randall, S. K., and Crowell, P. L. (2003) Enhanced cell cycle progression and down regulation of p21Cip1/Waf1 by PRL tyrosine phosphatases. Cancer Lett., 202: 201-211.
• Crowell, P.L.*, Schmidt, C.M.*, Yip-Schneider, M.T., Savage, J.J., Hertzler, D.H. II, and Cummings, W.O. (2006) The role of cyclooxygenase-2 in hamster and human pancreatic tumorigenesis. Neoplasia 8:437-445. *Co-first authors
• Dumaual, C. M., Sandusky, G. E., Crowell, P. L., and Randall, S. K. (2006) Cellular localization of PRL-1 and PRL-2 gene expression in normal adult human tissues. J. Histochemistry and Cytochemistry 54: 1401 – 1412.
• Wiseman, D. A., Werner, S. R., and Crowell, P. L. (2006) Cell cycle arrest by the isoprenoids perillyl alcohol, geraniol, and farnesol is mediated by p21Cip1 and p27Kip1 in human pancreatic adenocarcinoma cells. J. Pharmacol. Exper. Therapeutics, in press.

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Brittney-Shea Herbert, Ph.D.

Positions

• Assistant Professor of Medical and Molecular Genetics
• Member of the Indiana University Melvin and Bren Simon Cancer Center

Address
Dept of Medical and Molecular Genetics
Indiana University Melvin and Bren Simon Cancer Center
Indiana University School of Medicine
975 W. Walnut St., IB 242
Indianapolis, IN 46202

Phone: (317) 278-6147
Fax: (317) 274-1069
Email: brherber@iupui.edu

Research Interests

The major research interest of my laboratory is in the role of telomerase in aging and cancer. Telomerase is a ribonucleoprotein complex that aids in the maintenance of telomeres. Telomeres provide a protective cap for the ends of chromosomes to prevent fusions and recognition as damaged DNA. Most somatic cells do not contain telomerase activity. However, telomerase activity is present in cells with the indefinite potential to replicate, such as stem, germ, and cancer cells. As telomerase can play a role in the replicative potential of stem cells, which is currently undergoing intensive research, it is important to understand how telomerase is regulated. Furthermore, telomerase expression may be used in the study of tissue regeneration. Induced expression of telomerase results in the immortalization of normal cells and these cells can be expanded and induced to differentiate. Conversely, inhibition of telomerase in cancer cells results in the reduction of cell growth, tumor formation, and metastases in vitro and in vivo. Therefore, telomerase represents not only a tool for regenerative biology, but also a target for cancer therapy. We are currently investigating the role of telomerase in cell growth and the replicative potential in normal and cancerous cells using natural/ synthetic compounds or DNA/RNA molecules (such as thio-phosphoramidates and microRNAs) that can regulate telomerase activity.

Recent Publications

• Herbert B-S, Hochreiter AE, Wright WE, Shay JW (2006) Non-radioactive detection of telomerase activity using the Telomeric Repeat Amplification Protocol (TRAP). Nature Protocols 1: 1583-1590.
• Lewis C*, Herbert B-S* (*co-first authors), Bu D, Halloway S, Beck A, Shadeo A, Ashfaq R, Brekken R, Lam W, Shay JW, Euhus D (2006) Telomerase immortalization of human mammary epithelial cells derived from a BRCA2 mutation carrier. Breast Cancer Research and Treatment 99:103-115.
• Herbert B-S, Gellert G, Hochreiter A, Pongracz K, Wright WE, Zielinska D, Chin A, Harley CB, Shay JW, Gryaznov SM (2005) Lipid modification of GRN163, an N3’?P5’- thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition. Oncogene 24:5262-5268.
• Hochreiter AE, Xiao H, Goldblatt EM, Gryaznov SM, Miller KD, Badve S, Sledge GW, Herbert B-S (2006) The telomerase template antagonist GRN163L disrupts telomere maintenance, tumor growth and metastasis of breast cancer. Clinical Cancer Research 12: 3184-3192.
• Gomez-Millan J, Goldblatt EM, Gryaznov S, Mendonca MS, Herbert B-S (2007). Specific telomere dysfunction induced by GRN163L increases radiation sensitivity in breast cancer cells. International Journal of Radiation Oncology, Biology, Physics 67: 897-905.