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David A. Jones

Associate Professor of Oncological Sciences and of Medicinal Chemistry

B.S. University of Michigan, Ann Arbor

Ph.D. University of Colorado, Denver

Research

References

david.jones@hci.utah.edu

David Jones' Lab Page

David Jones' PubMed Literature Search

Research

Colorectal cancer is the third most common malignancy in terms of new cases and deaths among men and women in the United States. The past fifty years have seen only marginal improvement in survival from this disease. My laboratory focuses on defining the signaling pathways that control normal intestinal cell development and that, when disrupted, promote colon cancer formation. Our approaches rely on genomic analyses of human tumor specimens in juxtapositon with the genetic manipulation of signaling pathways in zebrafish as a model system for studying intestinal developmental.    

Much of our work centers around gaining an understanding of the tumor suppressor known as APC. Mutations in APC, or in its regulatory target, β -catenin, are thought to cause colon neoplasms by promoting proliferation and preventing proper differentiation of colonocytes. However, our understanding of the mechanisms that control colonocyte differentiation is limited. In this respect, we have found using microarray analysis that human colon adenomas and carcinomas show a profound deficiency of retinoic acid biosynthetic enzymes. Furthermore, re-introduction of wildtype APC into an APC-deficient colon cancer cell lines increased retinoic acid production. Our observations suggest a novel model wherein APC promotes enterocyte differentiation by controlling retinoic acid biosynthesis. Despite these important findings using human tissues, the inability to culture and genetically perturb normal human enterocytes hampers studies aimed at testing the genetic relationship between APC and retinoic acid in the gut.

In view of this, we continue our studies examining the our hypotheses regarding intestinal cell differentiation using zebrafish as a model system. In recently published and ongoing studies, we confirmed the predicted relationship between APC and retinoic acid. We found that knock down of either APC or retinoic acid biosysnthesis, in zebrafish embryos, results in defects in structures known to require retinoic acid. In addition, zAPC or retinoic acid knockout fish develop intestines that lack columnar epithelial cells and fail to express the differentiation marker intestinal fatty acid binding protein (i-FABP). Treatment of either APC mutant embryos with retinoic acid rescues the defective phenotypes. This implicates retinoic acid in intestinal differentiation and, for the first time, places retinoic acid downstream of the APC tumor suppressor.

We are also interested in the relationship between APC and the silencing of gene expression by the process of DNA methylation. DNA methylation occurs at cytosines residing within CpG dinucleotides. The methylation state of CpG islands within gene promoter regions often causes silencing of that particular gene. Alterations in developmentally established methylation patterns may, therefore, alter the gene expression patterns within tissues and cause or promote disease.   We are currently studying the interaction between APC and DNA methylation as well as the potential of targeting enzymes that establish and interpret methylation patterns with drugs that reactivate gene expression in tumors.

 

 

 

 

 

 

 

 

 

 

 

 

 

Microarray analysis of colon tumor versus normal colon.

 

References