Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells

Cancer Cell. 2010 Nov 16;18(5):448-58. doi: 10.1016/j.ccr.2010.10.020.

Abstract

Mutational activation of KRas is the first and most frequently detected genetic lesion in pancreatic ductal adenocarcinoma (PDAC). However, the precise role of oncogenic KRas in the pathogenesis of PDAC is not fully understood. Here, we report that the endogenous expression of oncogenic KRas suppresses premature senescence in primary pancreatic duct epithelial cells (PDEC). Oncogenic KRas-mediated senescence bypass is conferred by the upregulation of the basic helix-loop-helix transcription factor Twist that in turn abrogates p16(INK4A) induction. Moreover, the KRas-Twist-p16(INK4A) senescence bypass pathway is employed in vivo to prevent inflammation-associated senescence of pancreatic ductal epithelium. Our findings indicate that oncogenic KRas could contribute to PDAC initiation by protecting cells from entering a state of permanent growth arrest.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal / genetics*
  • Cell Proliferation
  • Cells, Cultured
  • Cellular Senescence / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Pancreatic Ducts / cytology*
  • Pancreatic Neoplasms / genetics*
  • Pancreatitis / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Proto-Oncogene Proteins p21(ras) / physiology*
  • RNA, Messenger / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism
  • beta-Galactosidase / analysis

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • Nuclear Proteins
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • Twist-Related Protein 1
  • Twist1 protein, mouse
  • beta-Galactosidase
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)