Cellular Functions of HPV16 E5 Oncoprotein during Oncogenic Transformation

Abstract

The human papillomavirus (HPV) is recognized as the main etiologic agent associated with cervical cancer. HPVs are epitheliotropic, and the ones that infect the mucous membranes are classified into low-risk (LR) and high-risk (HR) types. LR-HPVs produce benign lesions, whereas HR-HPVs produce lesions that may progress to cancer. HR-HPV types 16 and 18 are the most frequently found in cervical cancer worldwide. E6 and E7 are the major HPV oncogenic proteins, and they have been profusely studied. Moreover, it has been shown that the HPV16 E5 (16E5) oncoprotein generates transformation, although the molecular mechanisms through which it carries out its activity have not been well defined. In contrast to E6 and E7, the E5 open reading frame is lost during the integration of the episomal HPV DNA into the cellular genome. This suggests that E5 acts at the early stages of the transformation process. In this review, we focused on the biochemical characteristics and functions of the HPV E5 oncoprotein, mainly on its association with growth factor receptors and other cellular proteins. Knowledge of the HPV E5 biology is important to understand the role of this oncoprotein in maintaining the viral cycle through the modulation of proliferation, differentiation, and apoptosis, as well as the alteration of other processes, such as survival, adhesion, migration, and invasion during early carcinogenesis. Finally, we summarized recent research that uses the E5 oncoprotein as a therapeutic target, promising a novel approach to the treatment of cervical cancer in its early stages.

It Takes Two to Tango: A Review of Oncogenic Virus and Host Microbiome Associated Inflammation in Head and Neck Cancer

“…Stimulation of EGFR also activates down steam products including prostaglandins, COX2, and PGE2, which promote angiogenesis through VEGF [61]. Although it has been demonstrated to prevent apoptosis in these cells, the E5 transcript is deleted relatively early in the infectious cycle, and therefore is not thought to contribute to carcinogenesis [62].…”

“…Additionally, studies of benign HPV diseases, specifically recurrent respiratory papillomatosis (RRP), have demonstrated E5-mediated downregulation of human leukocyte antigens [24]. Similarly, there is evidence of muted T-helper cell responses in RRP and condyloma acuminate [62]. In high-risk HPV, E5 downregulates other cell surface markers that would activate otherwise an immune response.…”

Genetic variability of the HPV16 early genes and LCR. Present and future perspectives

“…E5 is located between nucleotides 3850 and 4101, encoding a small hydrophobic protein of 78 amino acids (Fig. 1) (Refs [115][116][117]. The viral oncoprotein forms a hexamer that acts as ion channel pores located in the endoplasmic reticulum and Golgi apparatus membranes (Ref.…”

Two conserved amino acids differentiate the biology of high‐risk and low‐risk HPV E5 proteins

“…The human papillomavirus (HPV)-16 E5 (16E5) protein is a weak transforming protein that resides in membranes of the endoplasmic reticulum (ER) and modulates cell growth and viral replication. [1][2][3][4][5][6] 16E5 can self-associate both in vitro and in vivo and form oligomers by hydrophobic interactions. 7,8 E5 proteins are classified into E5α, E5β, E5γ, and E5δ using predictive approaches of the biochemical characteristics and protein evolution, where those of high-risk HPVs fall in the E5α category and those of low-risk fall in to the E5β, E5γ, or E5δ families.…”

“…The human papillomavirus (HPV)‐16 E5 (16E5) protein is a weak transforming protein that resides in membranes of the endoplasmic reticulum (ER) and modulates cell growth and viral replication 1–6 . 16E5 can self‐associate both in vitro and in vivo and form oligomers by hydrophobic interactions 7,8 .…”