Ski protein levels increase during in vitro progression of HPV16-immortalized human keratinocytes and in cervical cancer

Virology. 2013 Sep;444(1-2):100-8. doi: 10.1016/j.virol.2013.05.039. Epub 2013 Jun 27.

Abstract

We compared the levels of the Ski oncoprotein, an inhibitor of transforming growth factor-beta (TGF-β) signaling, in normal human keratinocytes (HKc), HPV16 immortalized HKc (HKc/HPV16), and differentiation resistant HKc/HPV16 (HKc/DR) in the absence and presence of TGF-β. Steady-state Ski protein levels increased in HKc/HPV16 and even further in HKc/DR, compared to HKc. TGF-β treatment of HKc, HKc/HPV16, and HKc/DR dramatically decreased Ski. TGF-β-induced Ski degradation was delayed in HKc/DR. Ski and phospho-Ski protein levels are cell cycle dependent with maximal Ski expression and localization to centrosomes and mitotic spindles during G2/M. ShRNA knock down of Ski in HKc/DR inhibited cell proliferation. More intense nuclear and cytoplasmic Ski staining and altered Ski localization were found in cervical cancer samples compared to adjacent normal tissue in a cervical cancer tissue array. Overall, these studies demonstrate altered Ski protein levels, degradation and localization in HPV16-transformed human keratinocytes and in cervical cancer.

Keywords: Cervical cancer; HPV16-mediated transformation; Human keratinocytes; Human papillomavirus; Ski; TGF-beta.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • DNA-Binding Proteins / analysis*
  • Female
  • Host-Pathogen Interactions*
  • Human papillomavirus 16 / growth & development*
  • Humans
  • Keratinocytes / chemistry*
  • Keratinocytes / virology*
  • Proto-Oncogene Proteins / analysis*
  • Transforming Growth Factor beta1 / metabolism
  • Uterine Cervical Neoplasms / chemistry*
  • Uterine Cervical Neoplasms / virology*

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Transforming Growth Factor beta1
  • SKI protein, human