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Phosphorylation of ribosomal protein S6 attenuates DNA damage and tumor suppression during development of pancreatic cancer.

Abstract
The signaling pathways that mediate the development of pancreatic ductal adenocarcinoma (PDAC) downstream of mutant Kras remain incompletely understood. Here, we focus on ribosomal protein S6 (rpS6), an mTOR effector not implicated previously in cancer. Phosphorylation of rpS6 was increased in pancreatic acinar cells upon implantation of the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) or transgenic expression of mutant Kras. To examine the functional significance of rpS6 phosphorylation, we used knockin mice lacking all five phosphorylatable sites in rpS6 (termed rpS6(P-/-) mice). Strikingly, the development of pancreatic cancer precursor lesions induced by either DMBA or mutant Kras was greatly reduced in rpS6(P-/-) mice. The rpS6 mutants expressing oncogenic Kras showed increased p53 along with increased staining of γ-H2AX and 53bp1 (Trp53bp1) in areas of acinar ductal metaplasia, suggesting that rpS6 phosphorylation attenuates Kras-induced DNA damage and p53-mediated tumor suppression. These results reveal that rpS6 phosphorylation is important for the initiation of pancreatic cancer.
AuthorsAbed Khalaileh, Avigail Dreazen, Areej Khatib, Roy Apel, Avital Swisa, Norma Kidess-Bassir, Anirban Maitra, Oded Meyuhas, Yuval Dor, Gideon Zamir
JournalCancer research (Cancer Res) Vol. 73 Issue 6 Pg. 1811-20 (Mar 15 2013) ISSN: 1538-7445 [Electronic] United States
PMID23361300 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • DNA Primers
  • Ribosomal Protein S6
  • Sirolimus
Topics
  • Animals
  • Base Sequence
  • DNA Damage
  • DNA Primers
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Knockout
  • Pancreatic Neoplasms (genetics, metabolism, pathology)
  • Phosphorylation
  • Polymerase Chain Reaction
  • Ribosomal Protein S6 (genetics, metabolism)
  • Sirolimus (pharmacology)

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