Cutaneous HPV23 E6 prevents p53 phosphorylation through interaction with HIPK2

PLoS One. 2011;6(11):e27655. doi: 10.1371/journal.pone.0027655. Epub 2011 Nov 16.

Abstract

Ultraviolet irradiation (UV) is the major risk factor for the development of skin cancer. Moreover, increasing evidence suggests cutaneotropic human papillomaviruses (HPV) from the beta genus to play a causal role as a co-factor in the development of cutaneous squamous cell carcinoma. Homeodomain-interacting protein kinase 2 (HIPK2) operates as a potential suppressor in skin tumorigenesis and is stabilized by UV-damage. HIPK2 is an important regulator of apoptosis, which forms a complex with the tumor suppressor p53, mediating p53 phosphorylation at Ser 46 and thus promoting pro-apoptotic gene expression. In our study, we demonstrate that cutaneous HPV23 E6 protein directly targets HIPK2 function. Accordingly, HPV23 E6 interacts with HIPK2 both in vitro and in vivo. Furthermore, upon massive UVB-damage HPV23 E6 co-localizes with endogenous HIPK2 at nuclear bodies. Functionally, we demonstrate that HPV23 E6 inhibits HIPK2-mediated p53 Ser 46 phosphorylation through enforcing dissociation of the HIPK2/p53 complex. In addition, HPV23 E6 co-accumulates with endogenous HIPK2 upon UV damage suggesting a mechanism by which HPV23 E6 keeps HIPK2 in check after UV damage. Thus, cutaneous HPV23 E6 prevents HIPK2-mediated p53 Ser 46 phosphorylation, which may favour survival of UV-damaged keratinocytes and skin carcinogenesis by apoptosis evasion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Apoptosis / radiation effects
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Nucleus / radiation effects
  • DNA Damage
  • Humans
  • Oncogene Proteins, Viral / metabolism*
  • Papillomaviridae*
  • Phosphorylation / radiation effects
  • Protein Transport / radiation effects
  • Protein-Serine-Threonine Kinases / metabolism*
  • Serine / metabolism
  • Skin / cytology
  • Skin / metabolism*
  • Skin / radiation effects
  • Skin / virology
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism*
  • Ultraviolet Rays

Substances

  • Carrier Proteins
  • Oncogene Proteins, Viral
  • Tumor Suppressor Protein p53
  • Serine
  • HIPK2 protein, human
  • Protein-Serine-Threonine Kinases