Molecular mechanisms of transformation by the human papillomaviruses

Abstract

A variety of studies have now indicated that the papillomaviruses associated with cervical carcinoma, HPV-16 and HPV-18, contain two genes (E6 and E7) which have transforming properties. These genes are generally expressed in cervical carcinoma cells. The HPV-16 E7 protein has recently been shown to be a multi-functional protein possessing both transcriptional modulatory and cellular transforming properties similar to those described for adenovirus E1A proteins (1). E7 is able to transactivate the adenovirus E2 promoter and can cooperate with an activated ras oncogene to transform primary baby rat kidney cells. The N-terminal 37 amino acids of all of the E7 proteins of the genital associated HPVs contain regions which are highly conserved and which are quite similar to portions of conserved domains 1 and 2 of adenovirus E1A. These domains in E1A are critical for cellular transformation properties and contain the amino acid sequences involved in binding the product of the retinoblastoma tumor suppressor gene (pRB). Results from a collaborative study with Ed Harlow and Nick Dyson (Cold Spring Harbor Laboratory) have shown that the E7 oncoprotein of HPV-16 can associate with the retinoblastoma gene product in vitro (2). The ability of the E7 proteins encoded by various HPVs to bind pRB has been examined using an in vitro complexing assay. E7 is not sufficient for transformation of human keratinocytes. The co-operation of the HPV-16 E6 and E7 genes has been shown to be important for transformation of these cells (3). Potential intracellular protein targets for E6 are being assessed.