Abstract

The majority of colorectal cancers are associated with somatic mutations of the APC tumor suppressor gene. Similarly, familial adenomatous polyposis (FAP) patients, who inherit germline APC mutations, develop hundreds of colorectal tumors. While it is thus clear that APC mutations play a critical role in the development of colorectal neoplasia, how APC normally functions to suppress tumorigenesis remains obscure. The studies proposed in this project are focused on three major areas and are designed to elucidate the mechanisms underlying APC function in normal and diseased states. 1) APC-Induced Apoptosis. Previous studies have shown that expression of APC in colorectal cancer cells can result in apoptosis. The role of APC-induced apoptosis will be further tested by determining the generality of this observation, by defining the regions of APC critical to this function and by identifying changes in gene expression associated with APC induced apoptosis. 2) APC and beta-Catenin. The discovery that beta-catenin binds to APC jjhas provided an important clue to APC's function. This interaction will be further explored by mapping the regions required for beta-catenin transformation, determining the effects of APC on beta-catenin mediated transformation and identifying catenin-like proteins that are present in normal colonic mucosa and bind to APC. 3) APC and the Wg/WNT Signaling Pathway. Two proteins that bind APC (beta-catenin and GSK3) function in the Wg/WNT signal transduction pathway and signaling in this pathway ultimately results in induction of transcription by beta-catenin/TCF complexes. They will evaluate the relationship between APC and this pathway by identifying the TCF family members that are expressed in colonic epithelial cells, determining the effects of APC on beta-catenin/TCF induced transcription, and elucidating the spectrum of genes induced by beta-catenin/TCF activated transcription. The combination of the above studies should provide important insights into APC's function.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA057345-08
Application #
2894947
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mohla, Suresh
Project Start
1992-09-01
Project End
2002-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Le, Dung T; Durham, Jennifer N; Smith, Kellie N et al. (2017) Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357:409-413
Holdhoff, Matthias; Cairncross, Gregory J; Kollmeyer, Thomas M et al. (2017) Genetic landscape of extreme responders with anaplastic oligodendroglioma. Oncotarget 8:35523-35531
Anglesio, Michael S; Papadopoulos, Nickolas; Ayhan, Ayse et al. (2017) Cancer-Associated Mutations in Endometriosis without Cancer. N Engl J Med 376:1835-1848
Hoang, Margaret L; Chen, Chung-Hsin; Chen, Pau-Chung et al. (2016) Aristolochic Acid in the Etiology of Renal Cell Carcinoma. Cancer Epidemiol Biomarkers Prev 25:1600-1608
Hoang, Margaret L; Kinde, Isaac; Tomasetti, Cristian et al. (2016) Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing. Proc Natl Acad Sci U S A 113:9846-51
Robles, Ana I; Traverso, Giovanni; Zhang, Ming et al. (2016) Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers. Gastroenterology 150:931-43
Tie, Jeanne; Wang, Yuxuan; Tomasetti, Cristian et al. (2016) Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med 8:346ra92
Roberts, Nicholas J; Norris, Alexis L; Petersen, Gloria M et al. (2016) Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer. Cancer Discov 6:166-75
Tie, J; Kinde, I; Wang, Y et al. (2015) Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol 26:1715-22
Jiao, Yuchen; Lumpkins, Kimberly; Terhune, Julia et al. (2015) Intraductal papillary mucinous neoplasm in a neonate with congenital hyperinsulinism and a de novo germline SKIL gene mutation. Pancreatology 15:194-6

Showing the most recent 10 out of 145 publications