EXPRESSION OF P16 INDUCES TRANSCRIPTIONAL DOWN-REGULATION OF THE RB GENE

The RE and p16(INK4A) tumor suppressor genes function in the same path way of cell cycle control. Previous evidence indicates that the p16(IN K4A) gene is transcriptionally repressed by the RE gene product, pRB. In this study using human ovarian cancer cell lines, we found that RE protein and mRNA were expressed at higher levels in cell lines lacking p16 than in those with normal p16. Since this suggests a potential ro le of p16 in regulating the cellular level of pRB, we studied the effe ct of wild-type p16(INK4A) on expression of the RE gene. Introduction of p16(INK4A), carried by an adenovirus vector,;into p16-negative cell lines dramatically decreased expression of RE protein and mRNA. Nucle i run-off assays demonstrated that p16 expression induced transcriptio nal downregulation of the RE gene. These results indicate that express ion of RE is inversely regulated by p16. The findings reveal a new dim ension of pRB-p16 interaction and should have implications for p16(INK 4A)-mediated gene therapy.