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

PLoS Pathog. 2020 Aug 19;16(8):e1008792. doi: 10.1371/journal.ppat.1008792. eCollection 2020 Aug.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / antagonists & inhibitors*
  • Cell Proliferation*
  • Cells, Cultured
  • Down-Regulation
  • Humans
  • Keratinocytes / immunology
  • Keratinocytes / pathology*
  • Keratinocytes / virology
  • Membrane Proteins / antagonists & inhibitors*
  • Mice
  • Mice, Transgenic
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism*
  • Papillomaviridae / isolation & purification
  • Papillomavirus E7 Proteins / genetics
  • Papillomavirus E7 Proteins / metabolism*
  • Papillomavirus Infections / complications*
  • Papillomavirus Infections / virology
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Skin Neoplasms / etiology*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • Carrier Proteins
  • E6 protein, Human papillomavirus type 16
  • ITFG1 protein, human
  • Membrane Proteins
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Repressor Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • oncogene protein E7, Human papillomavirus type 16

Associated data

  • figshare/10.6084/m9.figshare.12733427