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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / antagonists & inhibitors*
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Cell Proliferation*
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Cells, Cultured
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Down-Regulation
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Humans
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Keratinocytes / immunology
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Keratinocytes / pathology*
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Keratinocytes / virology
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Membrane Proteins / antagonists & inhibitors*
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Mice
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Mice, Transgenic
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Oncogene Proteins, Viral / genetics
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Oncogene Proteins, Viral / metabolism*
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Papillomaviridae / isolation & purification
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Papillomavirus E7 Proteins / genetics
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Papillomavirus E7 Proteins / metabolism*
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Papillomavirus Infections / complications*
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Papillomavirus Infections / virology
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Skin Neoplasms / etiology*
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Skin Neoplasms / metabolism
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Skin Neoplasms / pathology
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Carrier Proteins
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E6 protein, Human papillomavirus type 16
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ITFG1 protein, human
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Membrane Proteins
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Oncogene Proteins, Viral
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Papillomavirus E7 Proteins
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Repressor Proteins
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TP53 protein, human
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Tumor Suppressor Protein p53
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oncogene protein E7, Human papillomavirus type 16
Associated data
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figshare/10.6084/m9.figshare.12733427