Sustained extracellular signal-regulated kinase1/2 mitogen-activated protein kinase signalling is related to increased p21 expression in cholesteatoma epithelium

Acta Otolaryngol. 2005 Feb;125(2):134-40. doi: 10.1080/00016480410022813.

Abstract

Conclusion: These results show for the first time that the RAS/RAF/ERK1/2 MAPK signalling pathway is active and involved in p21-mediated cell cycle arrest in human cholesteatoma epithelium.

Objective: In a previous report we have demonstrated that the epithelium in human cholesteatoma is characterized by high p53-dependent p21 expression. The RAS/RAF/extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) signalling pathway can induce p21 expression and subsequent cell cycle arrest via p53-dependent or -independent mechanisms. We designed the present study to investigate whether the RAS/RAF/ERK1/2 MAPK signalling pathway is involved in p53-dependent and p21-mediated cell cycle arrest in human cholesteatoma.

Material and methods: A total of 18 cholesteatoma samples and 18 paired control retro-auricular skin samples were immunohistochemically stained for p53, p21, phosphorylated ERK1/2 (pERK1/2) and total ERK1/2. Positive cells were counted by means of digital image analysis. Double-label fluorescence immunohistochemistry was performed to demonstrate co-expression of p21 and pERK1/2.

Results: Protein expression of p53, p21 and pERK1/2 differed significantly between cholesteatoma epithelium and retro-auricular skin (p <0.01). In cholesteatoma, co-expression of p21 and pERK1/2 was prominent, whereas in retro-auricular skin there was hardly any co-expression. Positive correlations were found between p53 and p21 (p =0.003) and between p21 and pERK1/2 (p =0.013).

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Cell Cycle / genetics
  • Cell Cycle / physiology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / immunology
  • Cell Cycle Proteins / metabolism*
  • Cholesteatoma, Middle Ear / genetics
  • Cholesteatoma, Middle Ear / metabolism*
  • Cholesteatoma, Middle Ear / pathology
  • Cyclin-Dependent Kinase Inhibitor p21
  • Epithelium / metabolism
  • Epithelium / pathology
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / immunology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Genes, cdc / physiology
  • Humans
  • Immunohistochemistry
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / immunology
  • MAP Kinase Kinase Kinases / metabolism
  • Membrane Glycoproteins / metabolism
  • Mitogen-Activated Protein Kinase 1 / immunology
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / immunology
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinases / immunology
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation
  • Signal Transduction / genetics*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / immunology
  • raf Kinases / genetics
  • raf Kinases / metabolism

Substances

  • Antibodies, Monoclonal
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Membrane Glycoproteins
  • Tumor Suppressor Protein p53
  • raf Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • Ras-dependent mitogen-activated protein kinase kinase kinase