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Emanuel N. Maisel Professor of Oncology Professor of Internal Medicine Professor of Pathology Professor of Human Genetics |
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| 1504 BSRB, Box 2200 109 Zina Pitcher Place Ann Arbor, MI 48109 -2200 |
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In general terms, our research is focused on the means by which defects in selected signal transduction pathways contribute to cancer pathogenesis. Three areas of emphasis are summarized below:
APC/Beta-catenin Pathway Defects: APC (adenomatous polyposis coli) gene defects appear to have a pre-eminent role in the pathogenesis of colorectal adenomas and carcinomas in man: i) bi-allelic inactivating mutations in the APC gene are found in about 75% of sporadic adenomas and carcinomas; and ii) APC inactivation appears to play a critical initiating role in adenoma development in the inherited setting of familial polyposis and in sporadic colorectal tumors. The APC protein binds to the beta catenin (beta-cat) protein, and regulation of beta-cat is altered in tumor cells in which APC is inactive. Beta-cat has a key function in binding to TCF (T cell factor) transcription factors, and beta-cat/TCF complexes activate target genes in tumor cells with defective beta-cat regulation. We are presently employing various approaches to identify beta-cat/TCF-regulated genes in neoplastic cells, with the goal of assessing the contribution of these genes to the cancer phenotype using in vitro models as well as genetically engineered mouse models where the candidate target genes are somatically targeted, along with the Apc gene, in mouse colorectal epithelial tissues.
Defects in the CDX2 Pathway in Human Colorectal Cancer: The discovery of specific germline (constitutional) defects predisposing to tumor development in man and/or the mouse offers the possibility of highlighting and clarifying genes and mechanisms involved in sporadic tumor development. Mice heterozygous for inactivation of the caudal-related Cdx2 homeobox transcripion factor gene develop colonic polyps in which the epithelial cells lose CDX2 expression, consistent with a potential tumor suppressor function for CDX2, and loss of CDX2 expression is seen in some poorly differentiated colon carcinomas in man. Conversely, ectopic CDX2 expression in gastric epithelium of transgenic mice promotes intestinal metaplasia, and, in man, CDX2 expression is often seen in intestinal metaplasia arising in the stomach as well as gastric carcinomas. The data imply that the CDX2 protein functions as a critical regulator of proliferation and differentiation in gastrointestinal epithelial cells and defects in its function, either loss-of-function in colonic epithelial cells or gain-of-function in gastric epithelial cells, can promote neoplastic transformation. To better understand the contribution of CDX2 defects to the pathogenesis of gastrointestinal tumors, we are working to define specific cellular genes that are directly regulated by CDX2. We are also assessing the role of selected CDX2-regulated genes in proliferation, differentiation, and tumorigenic growth of gastrointestinal cancer cells. Finally, we have begun to explore the role of a limited number of high interest CDX2-regulated genes in the pathogenesis of intestinal and colonic tumors, using mouse genetic models.
p53-mediated Regulation of the miRNA34 Family: In response to varied cell stress signals, the p53 tumor suppressor protein activates various genes encoding proteins with functions in cell cycle control, DNA repair, senescence, and apoptosis. We found that the three-member miRNA34 (miR-34) family is directly regulated by p53 in cell lines and tissues. Using array-based approaches and algorithm predictions, we defined genes likely to be directly regulated by miR-34, with cell cycle regulatory genes being the most prominent class, though we also found that the Bcl-2 protein is regulated directly by miR-34. Expression of miR-34b/c was found to be dramatically reduced in about 40-50% of non-small cell lung cancers (NSCLCs) and restoration of miR-34 expression inhibited growth of NSLC cells. Taken together, the data suggest the miR-34s may be key effectors of p53 tumor suppressor function and their inactivation may contribute to certain cancers. We are pursuing further in-depth studies of miR-34 function in normal and cancer cells, including analysis of the phenotype of mice carrying alterations at the miR-34a locus.
2007 - Johns Hopkins Univ Soc of Fellows
2005 - DSR Sarma Lecturer in Oncologic Pathology, Univ Toronto
2003 - Association of American Physicians
2000 - Lynch Lecturer, University of Notre Dame, Dept of Biology
1998 - American Society for Clinical Investigation (Vice-Pres, 2003-4; Pres-Elect, 2004-5; Pres, 2005-6)
1992-95 - McDonnell Fellow in Molecular Medicine in Cancer Research, James S. McDonnell Fund
1990 - Alpha Omega Alpha Honor Medical Society (JHU School of Medicine)
1990 - Wilson S. Stone Award, U. of Texas, M.D. Anderson Cancer Center
1983 - Phi Beta Kappa (Johns Hopkins Univ)
1990 The Johns Hopkins University, Ph.D. Biology/Program in Human Genetics
1990 The Johns Hopkins University School of Medicine, M.D.
1983 The Johns Hopkins University, B.A. Biophysics
Van Mater D, Kolligs FT, Dlugosz A, Fearon ER. Transient activation of beta-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice. Genes Dev 2003, 17:1219-24.
Hinoi T, Loda M, Fearon ER. Silencing of CDX2 expression in colon cancer via a dominant repression pathway. J Biol Chem 2003, 278:44608-16.
Feng Y, Lee N, Fearon ER. TIP49 regulates ?-catenin-mediated neoplastic transformation and TCF-target gene induction via effects on chromatin remodeling. Cancer Res 2003, 63:8726-34.
Hinoi T, Gesina G, Akyol A, Kuick R, Hanash S, Fearon ER. CDX2 regulates expression of ceruloplasmin-related protein hephaestin in intestinal and colonic epithelium. Gastroenterology 2005, 128:946-61.
Winer IS, Bommer GT, Gonik N, Fearon ER. Lysine residues K19 and K49 of beta-catenin regulate its levels and function in T cell factor transcriptional activation and neoplastic transformation. J Biol Chem 2006, 281:26181-7.
Feng Y, Bommer GT, Winer I, Zhai Y, Lin HV, Cadigan KM, Cho KR, Fearon ER. Drosophila split ends homologue SHARP functions in a positive feedback loop to enhance Wnt/beta-catenin/TCF signaling and neoplastic transformation. Cancer Res 2007, 67:482-91.
Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE, Zhai Y, Giordano TJ, Qin ZS, Moore BB, MacDougald OA, Cho KR, Fearon ER. p53-mediated activation of miRNA34 candidate tumor suppressor genes. Current Biol 2007, 17:1298-1307.
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