The high-risk human papillomaviruses (HPVs) are associated with
carcinomas of the cervix and other genital
tumors. Previous studies have identified two viral
oncoproteins, E6 and E7, which are expressed in the majority of HPV-associated
carcinomas. The ability of high-risk HPV E6
protein to immortalize human mammary epithelial cells (MECs) has provided a single-gene model to study the mechanisms of E6-induced oncogenic transformation. In this system, the E6
protein targets the
p53 tumor suppressor protein for degradation, and mutational analyses have shown that E6-induced degradation of p53
protein is required for MEC immortalization. However, the inability of most dominant-negative p53 mutants to induce efficient immortalization of MECs suggests the existence of additional targets of the HPV E6
oncoprotein. Using the yeast two-hybrid system, we have isolated a novel E6-binding
protein. This
polypeptide, designated
E6TP1 (E6-targeted
protein 1), exhibits high homology to
GTPase-activating proteins for Rap, including SPA-1,
tuberin, and Rap1GAP. The
mRNA for
E6TP1 is widely expressed in tissues and in vitro-cultured cell lines. The gene for
E6TP1 localizes to chromosome 14q23.2-14q24.3 within a locus that has been shown to undergo loss of heterozygosity in
malignant meningiomas. Importantly,
E6TP1 is targeted for degradation by the high-risk but not the low-risk HPV E6
proteins both in vitro and in vivo. Furthermore, the immortalization-competent but not the immortalization-incompetent HPV16 E6 mutants target the
E6TP1 protein for degradation. Our results identify a novel target for the E6
oncoprotein and provide a potential link between HPV E6
oncogenesis and alteration of a
small G protein signaling pathway.