Defining the Role of SCCRO in Neddylation in vivo
Tadmiri Venkatesh, PhD and Bhuvanesh Singh, MD, PhD, FACS
Despite significant advancements in the diagnosis and treatment, only modest improvements in survival have been achieved for human cancers. Biologic treatments have provided the largest incremental increase in survival and as such there is pressing need for identifying novel targets. We cloned Squamous Cell Carcinoma Related Oncogene (SCCRO) in our laboratory as part of our analysis of amplification at 3q that is present in several human cancers. Our work to date shows that SCCRO plays an essential role in neddylation and cancer pathogenesis, establishing it as a therapeutic target. The precise mechanisms by which it promotes neddylation and the downstream pathway involved in SCCRO driven oncogenesis remain to be defined. Given the multiplicity of pathways that are regulated by neddylation, we elected to identify genes/pathways affected by SCCRO using a mouse developmental model.
While analysis of the SCCRO knockout mouse confirmed the functional importance of SCCRO in development and neddylation, the complex phenotype combined with compensation by SCCRO paralogues, complicated identification of the involved genes/pathways. To overcome this issue, we developed a Drosophila model to assess the functional role of SCCRO. This combined with the ease of manipulation of the fly genome makes Drosophila an ideal model for defining SCCRO’s function. This prokect takes advantage of the expertise of two established laboratories to determine the functional basis for SCCRO in neddylation and to begin to identify genes/pathways involved. The overall goal of the project is delineation of the specific role of SCCRO in neddylation. To achieve these goals we will combine biochemical, and animal studies in the following series of interrelated specific aims:
1. To define the role of SCCRO in Drosophila development.
2. Determine if human SCCRO can rescue the Drosophila SCCRO loss-of-function lethal phenotype.
3. To determine the role of SCCRO’s neddylation promoting activity in fly development.
4. To identify and characterize the cellular pathway/s in which SCCRO functions.
The basic knowledge of SCCRO function, optimized biochemical assays and the availability of reagents in the Singh laboratory combined with the expertise in Drosophila genetics and SCCRO mutant flies developed in the Venkatesh laboratory will allow a unique approach towards defining the function of a potentially important cancer related gene.