HMG-I/Y, a new c-Myc target gene and potential oncogene

The HMG-I/Y gene encodes the HMG-I and HMG-Y proteins, which function as ar chitectural chromatin binding proteins important in the transcriptional reg ulation of several genes. Although increased expression of the HMG-I/Y prot eins is associated with cellular proliferation, neoplastic transformation, and several human cancers, the role of these proteins in the pathogenesis o f malignancy remains unclear. To better understand the role of these protei ns in cell growth and transformation, we have been studying the regulation and function of HMG-I/Y. The HMG-I/Y promoter was cloned, sequenced, and su bjected to mutagenesis analysis. A c-Myc-Max consensus DNA binding site was identified as an element important in the serum stimulation of HMG-I/Y. Th e oncoprotein c-Myc and its protein partner Max bind to this site in vitro and activate transcription in transfection experiments. HMG-I/Y expression is stimulated by c-Myc in a Myc-estradiol receptor cell line in the presenc e of the protein synthesis inhibitor cycloheximide, indicating that HMG-I/Y is a direct c-Myc target gene. HMG-I/Y induction is decreased in Myc-defic ient fibroblasts. HMG-I/Y protein expression is also increased in Burkitt's lymphoma cell lines, which are known to have increased c-Myc protein. Like Myc, increased expression of HMG-I protein leads to the neoplastic transfo rmation of both Rat la fibroblasts and CB33 cells. In addition, Rat la cell s overexpressing HMG-I protein form tumors in nude mice. Decreasing HMG-I/Y proteins using an antisense construct abrogates transformation in Burkitt' s lymphoma cells. These findings indicate that HMG-I/Y is a c-Myc target ge ne involved in neoplastic transformation and a member of a new class of pot ential oncogenes.