The Role of Dlc1 Isoform 2 in K-Ras2G12D Induced Thymic CancerReport as inadecuate

The Role of Dlc1 Isoform 2 in K-Ras2G12D Induced Thymic Cancer - Download this document for free, or read online. Document in PDF available to download.

The Deleted in liver cancer one Dlc1 tumor suppressor gene encodes a RhoGTPase activating protein RhoGAP. The Dlc1 gene has multiple transcriptional isoforms and we have previously established a mouse strain containing a gene trap gt insertion, which specifically reduces the expression of the 6.1 kb isoform isoform 2. This gene trapped allele when homozygous results in embryonic lethality and the heterozygous gene trapped mice do not show an increased incidence of cancers, suggesting that cooperating oncogenic changes may be required for transformation. In the present work, we have studied the in vivo cooperation between oncogenic K-Ras2 and Dlc1 genes in tumourigenesis. We have observed an increase in invasive thymic cancers, including both thymomas and lymphomas, resulting in significantly shortened life spans in mice heterozygous for the gt Dlc1 allele and an inducible LSL-K-Ras2G12D allele compared with the LSL-K-Ras2G12D only mice. The heterozygous mice showed a high degree of metastasis in the lung. We have found tumour specific selective hypermethylation of the Dlc1 isoform 2 promoter and reduction of the corresponding protein expression in thymic lymphoma TL and thymic epithelial carcinoma TEC derived from the thymic tumours. The Dlc1 deficient thymic lymphoma cell lines exhibited increased trans-endothelial cell migration. TEC cell lines also exhibited increased stress fiber formation and Rho activity. Introduction of the three Dlc1 isoforms tagged with GFP into these cells resulted in different morphological changes. These results suggest that loss of expression of only isoform 2 may be sufficient for the development of thymic tumors and metastasis.

Author: Mohammad Golam Sabbir, Heather Prieditis, Esther Ravinsky, Michael R. A. Mowat



Related documents