The Human Papillomavirus 16 E7 Oncoprotein Attenuates AKT Signaling To Promote Internal Ribosome Entry Site-Dependent Translation and Expression of c-MYC

Abstract

While the role of high-risk human papillomavirus (HPV) oncoproteins E6 and E7 in targeting p53 and retinoblastoma (Rb) has been intensively studied, how E6 and E7 manipulate cellular signaling cascades to promote the viral life cycle and cancer development is less understood. Keratinocytes containing the episomal HPV-16 genome had decreased activation of AKT, which was phenocopied by HPV-16 E7 expression alone. Attenuation of phosphorylated AKT (pAKT) by E7 was independent of the Rb degradation function of E7 but could be ablated by a missense mutation in the E7 carboxy terminus, H73E, thereby defining a novel structure-function phenotype for E7. Downstream of AKT, reduced phosphorylation of p70 S6K and 4E-BP1 was also observed in E7-expressing keratinocytes, which coincided with an increase in internal ribosomal entry site (IRES)-dependent translation that enhanced the expression of several cellular proteins, including MYC, Bax, and the insulin receptor. The decrease in pAKT mediated by E7 is in contrast to the widely observed increase of pAKT in invasive cervical cancers, suggesting that the activation of AKT signaling could be acquired during the progression from initial productive infections to invasive carcinomas. IMPORTANCEHPV causes invasive cervical cancers through the dysregulation of the cell cycle regulators p53 and Rb, which are degraded by the viral oncoproteins E6 and E7, respectively. Signaling cascades contribute to cancer progression and cellular differentiation, and how E6 and E7 manipulate those pathways remains unclear. The phosphoinositol 3-kinase (PI3K)/AKT pathway regulates cellular processes, including proliferation, cell survival, and cell differentiation. Surprisingly, we found that HPV-16 decreased the phosphorylation of AKT (pAKT) and that this is a function of E7 that is independent of the Rb degradation function. This is in contrast to the observed increase in AKT signaling in nearly 80% of cervical cancers, which typically show an acquired mutation within the PI3K/AKT cascade leading to constitutive activation of the pathway. Our observations suggest that multiple changes in the activation and effects of AKT signaling occur in the progression from productive HPV infections to invasive cervical cancers.T he causative link between human papillomavirus 16 (HPV-16) infection and the development of cervical cancer is well established (reviewed in reference 1). High-risk alpha genera HPV E6 and E7 oncoproteins interact with and degrade p53 and retinoblastoma (Rb), respectively, to alter cell cycle regulation (reviewed in references 2, 3, and 4). However, less is known about the interaction of E6 and E7 with cellular proteins that manipulate cellular signaling cascades. We sought to examine the role of HPV-16, and specifically E7 (here 16E7), in manipulating cellular signaling pathways critical to the survival of the cell and initially focused upon the phosphoinositol 3-kinase (PI3K)/AKT pathway.AKT was originally identified as the causative agent in the acute transforming retrovi...

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WDHD1 facilitates G1 checkpoint abrogation in HPV E7 expressing cells by modulating GCN5

“…Previous studies have shown that HPV E6 and E7 oncogenes augment the activation of AKT [ 32 , 34 ]. Nonetheless, a recent study showed that HPV-16 E7 can attenuate pAKT signalling [ 35 ]. In addition, hypoxic AKT activation is observed under conditions of E6/E7 repression [ 36 ], which indicates that the hypoxic AKT activation is regulated by an E6/E7-independent mechanism, but the mechanism is unclear.…”