Human papillomavirus type 38 alters wild-type p53 activity to promote cell proliferation via the downregulation of integrin alpha 1 expression

Abstract

Tumor suppressors can exert pro-proliferation functions in specific contexts. In the beta human papillomavirus type 38 (HPV38) experimental model, the viral proteins E6 and E7 promote accumulation of a wild-type (WT) p53 form in human keratinocytes (HKs), promoting cellular proliferation. Inactivation of p53 by different means strongly decreases the proliferation of HPV38 E6/E7 HKs. This p53 form is phosphorylated at S392 by the double-stranded RNA-dependent protein kinase PKR, which is highly activated by HPV38. PKR-mediated S392 p53 phosphorylation promotes the formation of a p53/DNMT1 complex, which inhibits expression of integrin alpha 1 ( ITGA1 ), a repressor of epidermal growth factor receptor (EGFR) signaling. Ectopic expression of ITGA1 in HPV38 E6/E7 HKs promotes EGFR degradation, inhibition of cellular proliferation, and cellular death. Itga1 expression was also inhibited in the skin of HPV38 transgenic mice that have an elevated susceptibility to UV-induced skin carcinogenesis. In summary, these findings reveal the existence of a specific WT p53 form that displays pro-proliferation properties.

High-Risk Human Papillomavirus and Epstein–Barr Virus Coinfection: A Potential Role in Head and Neck Carcinogenesis

“…A 2.44-fold increase in the expression of the ITGB5 gene, which encodes the β5 integrin subunit, was reported in cervical cells upon L2 overexpression [ 19 ]. In contrast, it was reported that HPV38 E6/E7 proteins downregulate the expression of αvβ8 integrin in human keratinocytes [ 20 ].…”

IBtkα Activates the β-Catenin-Dependent Transcription of MYC through Ubiquitylation and Proteasomal Degradation of GSK3β in Cancerous B Cells

“…Cells were lysed in modified RIPA buffer (10 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM EDTA, 1% Igepal). Immunoprecipitation (IP) experiments were performed as previ-ously described [50,51]. Briefly, cells were lysed in RIPA buffer (50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 1 mM EDTA, 1% Igepal, 0.5% sodium deoxycholate).…”

Molecular Mechanisms of MmuPV1 E6 and E7 and Implications for Human Disease

“…Transgenic animal models for the cutaneous HPV8 and HPV38 associated with cancer in EV patients have documented the carcinogenic activities of these HPVs [ 21 , 22 , 23 , 24 , 31 , 32 , 33 , 34 ]. Transgenic mice that express the complete early region of HPV8 expressed from the K14 promoter spontaneously develop papillomas at a high frequency that progressed to cutaneous squamous cell carcinoma (cSCC) in a subset of these mice [ 21 ].…”

“…The cutaneous, beta and gamma HPVs lack E5 genes. The E6 and E7 proteins of some cutaneous HPVs have been demonstrated to display oncogenic activities in cell and transgenic animal-based studies [ 16 , 21 , 22 , 23 , 24 , 25 , 26 , 30 , 31 , 32 , 33 , 34 , 35 ]. Because of the pronounced species specificity of papillomaviruses, it has not been possible to perform pathogenesis studies by experimentally infecting laboratory animal with HPVs.…”