Oregon Health & Science University
Axin1 is a scaffold protein that regulates multiple signaling pathways including WntÎ²-Catenin, SAPK/JNK, TGFÎ², and p53. Axin1 also coordinates a degradation complex for c-Myc. c-Myc is a proto oncogene that belongs to a family of basic helix loop helix transcription factors and it is overexpressed in many cancers. This thesis seeks to investigate the role of Axin1 in regulating the c-Myc oncoprotein in leukemia and also provides insight into the role of Axin1 Exon 7 in binding to c-Myc and regulating its transcriptional activity. Axin1 has been characterized as a tumor suppressor and it is mutated in hepatocellular, colorectal and other cancers. c-Myc is known to be overexpressed in leukemia. Since Axin1 coordinates a destruction complex for c-Myc, I investigated the role of Axin1 in leukemia. Here, I show that increased Axin1 protein levels are able to decrease c-Myc protein levels in the U937 leukemia cell line and I also show that the U937 leukemia cell line preferentially expresses the variant 2 isoform of Axin1, which is less effective in regulating c-Myc. I also sequenced Axin1 in 26 leukemia patient samples and found many sequence variations of Axin1 and I show that Axin1 protein sequence changes are rare in leukemia. We have previously shown that Axin1 coordinates a degradation complex for c-Myc consisting of Gsk3Î², PP2A, Pin1, Axin1 and c-Myc. Preliminary protein truncation experiments suggested that Exon 7 of Axin1 is important for Axin1 binding to c-Myc. Based on these results, I investigated the role of Axin1 Exon 7 in binding and regulating c-Myc. Here, I show that Exon 7 of Axin1 contains a domain that is conserved across species and deletion of this conserved domain decreases Axin1 binding to c-Myc. Furthermore, I also show that Axin1 in which Exon 7 is deleted is specifically defective in regulating c-Myc while maintaining its activity towards Î²-Catenin. These findings further expand our understanding of Axin1âs role in regulating c-Myc in cancer and they provide tools that may help in discriminating Axin1âs role in different pathways.
Program in Cancer Biology
School of Medicine
Krishnamoorthy, Arun Kumar, "Role of Axin1 scaffold protein in regulating the c-myc onocoprotein" (2012). Scholar Archive. 715.