Deleted in liver cancer 1 (DLC1) in liver development and disease

University Of California At Davis, Davis CA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The establishment of an abnormal angioarchitecture via neovascularization is related to the pathological progression from hepatocyte damage to inflammation, fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and metastasis. My long term goal is to better understand the role of angiogenesis in the progression of liver disease to build foundation of knowledge to further develop anti-angiogenic therapies for blocking or slowing down this process. The current proposal focuses on the regulation of angiogenesis and cell migration by deleted in liver cancer 1 (DLC1), a RhoGAP containing tumor suppressor gene that interacts with members of the tensin family. DLC1 regulates cell migration through modulation of the actin cytoskeleton and focal adhesions. Multiple studies have demonstrated that the RhoGAP domain is necessary for the tumor suppressive function of DLC1, as well as the focal adhesion targeting domain, which is recruited by the Src Homology 2 (SH2) domains of tensins in a phosphotyrosine-independent fashion. I have also discovered that loss of DLC1 enhances angiogenesis by upregulating VEGF and plasminogen activator inhibitor 1 (PAI-1) expression. Knockout mouse studies have indicated an essential role for DLC1 in mouse embryonic development as homozygous mutant embryos die before 10.5 days. Based on these findings, I hypothesis that DLC1 may have roles in liver development and the progression of liver disease; to this end I have produced a DLC1 conditional knockout mouse. To address this overall hypothesis I will use in vivo and in vitro approaches in the following specific aims: 1) To characterize the role of DLC1 in liver development and function using a DLC1 conditional knockout mouse model. 2) To systematically determine the expression of DLC1 and the interacting tensin focal adhesion molecules during induced liver damage, and the susceptibility to liver disease progression of DLC1 knockout mice. 3) To investigate the regulatory activity of tensin family members on DLC1's RhoGAP activity and consequent regulation of angiogenesis and cell migration. An understanding of the functional impact of DLC1 in liver development and disease progression will help find new early diagnosis or therapeutic targets for liver disease.