Colon cancer is the second leading cause of cancer related deaths in the United States. Aberrant activation of the canonical Wnt/(-catenin pathway occurs in almost all colorectal cancers and contributes to colon cancer growth, invasion and survival. Although dysregulated (-catenin activity drives early events in colon tumorigenesis, additional genetic perturbations are required to articulate the full scope of malignant disease. To identify genes that both modulate (-catenin activity and are essential for colon cancer cell survival, we conducted two RNAi-based loss-of-function screens in human colon cancer cell lines. When we evaluated the genes identified in these screens with an analysis of whole genome copy-number alterations in colon cancer specimens, we found that one of these genes, CDK8, which encodes a kinase member of the mediator complex, is highly expressed in a subset of human colon tumors and is located at 13q12.13, a region of recurrent amplification in 47% of colon cancers. Preliminary results show that CDK8 activates (-catenin mediated transcription and oncogenically transforms murine fibroblasts in vitro and in vivo. The kinase activity of CDK8 is required for both these properties. Here I propose to extend my initial observations by 1. Determining transcriptional components and targets that are necessary for CDK8 mediated oncogenicity; 2. Identifying the target phospho-protein that mediates the oncogenic effect of CDK8; 3. Analyzing the diagnostic and therapeutic potential of CDK8 in human cancer. ? ? Dr. Ron Firestein, the principal investigator, is an M.D., Ph.D., who has completed residency and fellowship training in Pathology and wishes to develop an independent scientific career focusing on identifying and characterizing oncogenic pathways in cancer development and progression. Dr. Firestein is receiving his training in the laboratory of Dr. William Hahn at Dana Farber Cancer Institute, with additional access to the resources of the Broad Institute of Harvard and M.I.T. ? ? LAY SUMMARY: We have identified a novel activator of colon cancer growth called """"""""CDK8"""""""". This work will define the mechanism of CDK8 activation in human colon cancer using biochemistry and animal models and will explore the diagnostic and therapeutic potential of CDK8 as cancer biomarker. This research has significant potential to lead us to decisive new treatments for human colon cancer. ? ? ?
| Firestein, Ron; Shima, Kaori; Nosho, Katsuhiko et al. (2010) CDK8 expression in 470 colorectal cancers in relation to beta-catenin activation, other molecular alterations and patient survival. Int J Cancer 126:2863-73 |
| Kim, So Young; Dunn, Ian F; Firestein, Ron et al. (2010) CK1epsilon is required for breast cancers dependent on beta-catenin activity. PLoS One 5:e8979 |
