Appointment period: 7/1/2010 to 6/30/2012

Award: Research Career Development Award (NIH/NIDDKD) #K01DK097291, entitled "Deleted in liver cancer 1 (DLC1) in liver development and disease", September 2013-July 2018

Project

Generation and characterization of DLC-1 prostate conditional knockout mice

Background:

Deleted in liver cancer-1 (DLC-1) is a tumor suppressor gene that is frequently deleted in a variety of cancers. Re-expression of DLC-1 in cancer cells regulates the structure of actin cytoskeleton and focal adhesions and significantly inhibits tumor cell growth. This tumor suppressive function relies on DLC-1’s RhoGTPase activating protein (RhoGAP) activity and steroidogenic acute regulatory (StAR)-related lipid transfer (SART) domain, as well as its focal adhesion localization, which is recruited by the Src Homology 2 (SH2) domains of tensins in a phosphotyrosine-independent fashion.

The knockout mouse studies have indicated an essential role for DLC-1 in mouse embryonic development. Homozygous mutant embryos die before 10.5 days postcoitus with defects in the neural tube, brain, heart, and placenta. Fibroblasts isolated from DLC-1 mutant embryos contain disrupted actin filaments and fewer focal adhesions. The embryonic fibroblast study results confirmed the role of DLC-1 in regulating actin cytoskeleton and focal adhesion structures. However, the early lethality of DLC-1 null embryos limited further study on its role as a tumor suppressor. The tissue specific deletion of DLS-1 in mice will provide more information on its roles in various cancers and may provide good animal models for those relevant human cancers.

Specific Aims:

• Aim 1: Generation of DLC-1 loxP targeting construct, IS cells and mice, as well as prostate specific knockout mice.
• Aim 2: Assessment of the effects of DLC-1 deletion in vivo on prostate development, morphology, angiogenesis, tumorigenesis, the expression of focal adhesion components and other relevant biochemical markers, and prostatic cell apoptosis and proliferation.