Differential Regulation of Cutaneous Oncoprotein HPVE6 by wtp53, Mutant p53R248W and ΔNp63α is HPV Type Dependent

Abstract

UV exposure and p53 mutations are major factors in non-melanoma skin cancer, whereas a role for HPV infections has not been defined. Previous data demonstrated the wtp53-mediated degradation of cutaneous HPV20E6 by caspase-3. ΔNp63α and hot-spot mutant p53R248W conveyed a protective effect on HPV20E6 under these conditions. We demonstrate a differential regulation by wtp53 of the E6 genes of cutaneous types HPV4, HPV5, HPV7, HPV27, HPV38, HPV48, HPV60 and HPV77. Caspase- or proteasome-mediated down-regulation was HPV type dependent. Mutant p53R248W up-regulated expression of all these E6 proteins as did ΔNp63α except for HPV38E6 which was down-regulated by the latter. None of these cellular proteins affected HPV41E6 expression. Ectopic expression of both mutp53R248W and ΔNp63α in the normal NIKS keratinocyte cell line harbouring endogenous p53 and p63however led to a down-regulation of HPV20E6. We demonstrate that HPV20E6 expression in these cells is modulated by additional, yet unidentified, cellular protein(s), which are not necessarily involved in apoptosis or autophagy. We further demonstrate proliferation of HPV20E6-expressing keratinocytes. Levels of proteins involved in cell cycle control, cyclin-D1, cdk6 and p16INK4a, phosphorylated pRB, as well as c-Jun and p-c-Jun, were all increased in these cells. HPV20E6 did not compete for the interaction between p16INK4a with cyclin-D1 or cdk6. Phosphorylation of pRB in the HPV20E6 expressing cells seems to be sufficient to override the cytokenetic block induced by the p16INK4a/pRB pathway. The present study demonstrates the diverse influence of p53 family members on individual cutaneous HPVE6 proteins. HPV20E6 expression also resulted in varying protein levels of factors involved in proliferation and differentiation.

Mapping of Betapapillomavirus Human Papillomavirus 5 Transcription and Characterization of Viral-Genome Replication Function

“…However, this finding was not confirmed when E6/E7 was expressed in HaCat keratinocytes (54). It has been demonstrated that wt p53 induces the downregulation of E6 from HPV5, HPV20, and HPV38 (55), supporting the notion of a role for E6 in oncogenesis. In organotypic cultures of betaHPVs, E6 and E7 cause a delay in differentiation and altered keratinocyte growth (56,57).…”

Association Between β-Genus Human Papillomavirus and Cutaneous Squamous Cell Carcinoma in Immunocompetent Individuals—A Meta-analysis

“…However, HPV 20 has been shown to upregulate the p16INK4a and Akt–PI3K pathway, interfering with the cell cycle involved in progression to basal cell carcinoma. It is also known that the E6 proteins of HPV 20 can prevent UV-treated keratinocytes from undergoing apoptosis, while HPV38 E7 can degrade pRb increasing the lifespan of human keratinocytes by deregulating the cell cycle . In addition, the activation of nuclear factor kappa beta is believed to protect β-HPV immortalized human keratinocytes against tumor necrosis factor (TNF) and UV-mediated apoptosis .…”

HPV disease transmission protection and control

“…Oncogenic activities of the E6 and E7 proteins includes p53 sequestration, pRB binding, interference with DNA damage response pathways, disruption of cell cycle and cell division pathways, and immune evasion (reviewed in 5 51 102 ). An oncogenic role for some betapapillomaviruses such as HPV5 and HPV8 includes important co-factors such as UV-damage and include p53 modulation 65 103 . Untreated HPV-associated cancers can progress to malignant cancers that are locally invasive, difficult to treat, and often lead to death of the host.…”

“…The oncogenic potential of members of the betapapillomaviruses are hypothesized to require co-factors including UV light and p53 polymorphisms 123 . The roles of the viral oncogenes in these instances include activation of telomerase and extension of cell life span via E6 124 , and a potential cancer correlation with E6 and polymorphisms in p53 103 123 .…”