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.
Highlights
Cutaneous papillomaviruses (HPV) have been associated with the pathogenesis of non-melanoma skin cancer
The present study demonstrates a differential regulation of the E6 genes of cutaneous types HPV4, HPV5, HPV7, HPV27, HPV38, HPV48, HPV60 and HPV77 by wtp53
HPV infection, UV-exposure and mutations in wtp53 have been considered as interacting factors in the pathogenesis of nonmelanoma skin cancer
Summary
Cutaneous papillomaviruses (HPV) have been associated with the pathogenesis of non-melanoma skin cancer. E6 gene expression of several cutaneous HPV types protected keratinocytes from UV-B induced apoptosis [34,35,36] by mediating degradation [34] or a reduction in the levels of pro-apoptotic Bak [37] and thereby preventing the release of pro-apoptotic factors from mitochondria [38]. We demonstrated that p53-mediated caspase-dependent degradation of HPV20E6 was rescued by mutant p53R248W and DNp63a and other unknown proteins involved in proteasome degradation [13]. We investigated whether similar interactions between mutant p53R248W, wtp and DNp63a with E6 of other cutaneous HPV types occurred, as we had previously demonstrated a type specific, rather than genusor species-specific UV-induced activation or suppression of a number of cutaneous HPV promoters [36,39]. Caspase- or proteasome-mediated downregulation was HPV type dependent The majority of these E6 proteins were upregulated by both mutant p53R248W and DNp63a. Phosphorylation of pRB in the HPV20E6 expressing cells seems to be sufficient to override the cytokenetic block induced by the p16INK4a/pRB pathway
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