Our research aims at the characterization of new steroid hormone receptors and steroid hormone receptor-related proteins. SHRs mediate the complex biological effects of steroid during growth, development, and other physiological processes. An SHR is activated by binding a specific steroid hormone. This activated steroid-receptor complex recognizes specific DNA sequences which in several cases have been shown to be enhancers. The combination of specific SHRs and steroid-inducible genes located on active chromatin defines the response of a cell to a specific hormone. Given the numerous steroid hormones active in the human and their importance in cell growth, differentiation, and many other metabolic processes, one can also expect a number of steroid hormone receptor genes to be involved in metabolic diseases and tumor development. This is supported by two recent findings. cloning of three steroid hormone receptors revealed a strong homology amongst these proteins but also showed that similarly high homology exists between steroid hormone receptors and the viral erbA oncogene product. Analysis of a hepatitis B virus (HBV) DNA integration site in a hepatocellular carcinoma (HCC) showed that the HBV integration places the viral sequence next to a cellular DNA sequence (called here HBV-HC) which codes for a DNA-binding domain of a steroid hormone receptor. Expression of the HBV-HC gene could have led to the development of the particular HCC. The HBV-HC sequence is not expressed in normal liver. To learn more about the HBV-HC gene and erbA-related genes in the human, we have screened human cDNA libraries from testis and placenta for the presence of erbA and HBV-HC-like clones and were able to isolate such clones. We will now determine the primary sequence of these gene products, examine their tissue and developmental expression, and their possible involvement in malignancies. We will also determine how these proteins function and how a normal steroid hormone receptor can be converted by mutation into a gene activator with tumor-promoting potential. Our goals also include the isolation and characterization of other new members of the steroid hormone receptor gene family. The proposed studies will enhance our knowledge about this important class of regulatory proteins and how they are involved in normal cell regulation and in tumor development.