Human papillomavirus type 16 E6 inhibits p21 WAF1 transcription independently of p53 by inactivating p150 Sal2

Abstract

HPV16 E6 deregulates G1/S cell cycle progression through p53 degradation preventing transcription of the CDK inhibitor p21 WAF1. However, additional mechanisms independent of p53 inactivation appear to exist. Here, we report that HPV16 E6 targets the cellular factor p150 Sal2, which positively regulates p21 WAF1 transcription. HPV16 E6 associates with p150 Sal2, inducing its functional inhibition by preventing its binding to cis elements on the p21 WAF1 promoter. A HPV16 E6 mutant, L110Q, which was unable to bind p150 Sal2, did not affect the ability of the cellular protein to bind p21 WAF1 promoter, underlining the linkage between these events. These data describe a novel mechanism by which HPV16 E6 induces cell cycle deregulation with a p53-independent pathway. The viral oncoprotein targets p150 Sal2, a positive transcription regulator of p21 WAF1 gene, preventing G1/S arrest and allowing cellular proliferation and efficient viral DNA replication.