Abstract #1867: HMTV Env protein interaction network overlaps with JAK/STAT signaling

Our laboratory reported that mouse mammary tumor virus (MMTV) like sequences were present in 38% of American Women breast cancers, but were absent in adjacent normal tissues. Furthermore, the complete proviral structure with 95% homology to MMTV was determined in two breast cancers. Viral particles with the typical characteristics of beta retroviruses have been isolated from primary cultures of human breast cancer cells. We have named this virus human mammary tumor virus (HMTV). Recently the surface (SU) domain of the envelope protein (ENV) of certain retroviruses has been shown to initiate a cell transformation by signaling cascade. We are investigating molecular mechanism(s) of cell transformation by HMTV. In this study we focus on the role of the SU domain of the HMTV Env. The main approach of our research is to detect the protein interaction network of SU. Using the yeast two hybrid system, we have identified genes which clustered in two major networks: one promoting cell growth, the other involved in carcinogenesis according to the Ingenuity Pathway Analysis (IPA). Identified candidates were tested for direct binding with SU protein by in vitro translation and subsequent immunoprecipitation IP assay. After superimposing both protein networks we indentified five common genes involved in JAK/STAT signaling: WSB1, SKAP2, SOCS3, PRMT5 and FUS. Amino acid sequence analysis reveled SOCS (suppressors of cytokine signaling) box in SOCS3 and WSB1. SOCS proteins are potent endogenous inhibitors of JAK/STAT signaling. Other genes like PRMT's can both negatively and positively regulate protein-protein interactions by methylating an arginine residue and activating JAK/STAT signaling. Next step of our research is focused on identification of alterations that causes SU protein on these five genes and subsequently JAK/STAT signaling. We are also performing cell culture co-transfection assays to address this issue. Results from these experiments are providing significant new insights about the role of ENV in breast cancer pathogenesis.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1867.