Human papillomaviruses, cervical cancer and cell polarity

Abstract

Human papillomaviruses (HPVs) are the causative agents of a number of human cancers, of which cervical cancer is the most important. This occurs following persistent infection with a limited number of viral subtypes and is characterized by continued expression of the viral E6 and E7 oncoproteins. A unique characteristic of the cancercausing HPV types is the presence of a PDZ recognition motif on the carboxy terminus of the E6 oncoprotein. Through this motif, E6 directs the proteasome-mediated degradation of cellular proteins involved in the regulation of cell polarity and in cell proliferation control. These include components of the Scrib and Par polarity complexes, as well as a number of other PDZ domaincontaining substrates. Thus, PVs are now providing novel insights into the functioning of many of these cellular proteins, and into which of these functions, in particular, are relevant for maintaining normal cellular homeostasis. In this review, we discuss the biological consequences of papillomaviral targeting of these cell polarity regulators, both with respect to the viral life cycle and, most importantly, to the development of HPV-induced malignancy.

Polarity proteins in migration and invasion

“…It is not surprising to find that loss of or decreased Scrib, Dlg or Lgl correlates with more invasive tumors as these molecules are essential for maintaining directed migration (Humbert et al, 2006). Interestingly, the E6 oncoprotein from HPV16 and HPV18 papilloma viruses, which are responsible for a vast majority of cervical cancers, target Scrib and Dlg for degradation ((Thomas et al, 2005), also reviewed in Thomas et al, 2008). Von-Hippel-Lindau, a tumor suppressor involved in the von-Hippel-Lindau disease, which leads to the development of hemagioblastoma, clear-cell renal carcinoma and pheochromocytomas (Kaelin, 2005), interacts with the Par3-Par6-aPKC complex and regulates microtubule network organization (Schermer et al, 2006).…”

The epithelial polarity program: machineries involved and their hijacking by cancer

“…Cancer promoting viruses, such as human papilloma virus (HPV), also utilize the Scribble and Par complexes for oncogenic purposes (see Thomas et al, 2008). HPV destabilizes the Crumbs 3-Par complex, required for tight junction formation by interacting with PATJ and targeting this protein for degradation (Storrs and Silverstein, 2007).…”

Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module

“…Targeting of Scribble/Dlg by oncoviral proteins Scribble, Dlg and Lgl have been linked to the development of mammalian tumours, most directly by the property of being targeted by oncoviral proteins (reviewed by Thomas et al, 2008 andJavier, 2008). Human papillomavirus (HPV) infections are associated with over 90% of cervical cancers.…”

“…E6 and E7 oncoproteins are the primary mediators of this malignancy, arising from interactions with key regulators of growth and proliferation, most notably the tumour suppressors p53 and pRb Munger et al, 2001). E6 oncoproteins from high-risk virus types (HPV-16 and HPV-18), but not from lowrisk virus types, also interact with a set of PDZ domaincontaining proteins, including Scribble, Dlg1 and Dlg4 (reviewed by Thomas et al, 2008). This interaction is mediated by a short stretch of four amino acids in the C terminus of E6 (Kiyono et al, 1997;Lee et al, 1997).…”