1. Phosphorylation of Ribosomal Protein S6 Attenuates DNA Damage and Tumor Suppression during Development of Pancreatic Cancer
- Author
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Oded Meyuhas, Gideon Zamir, Norma Kidess-Bassir, Avital Swisa, Roy Apel, Abed Khalaileh, Yuval Dor, Areej Khatib, Anirban Maitra, and Avigail Dreazen
- Subjects
Cancer Research ,DNA damage ,DMBA ,Biology ,medicine.disease_cause ,Polymerase Chain Reaction ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Pancreatic cancer ,medicine ,Animals ,Phosphorylation ,neoplasms ,PI3K/AKT/mTOR pathway ,DNA Primers ,030304 developmental biology ,Mice, Knockout ,Sirolimus ,Mice, Inbred ICR ,Ribosomal Protein S6 ,0303 health sciences ,Base Sequence ,Cancer ,medicine.disease ,Molecular biology ,digestive system diseases ,Mice, Inbred C57BL ,Pancreatic Neoplasms ,Oncology ,030220 oncology & carcinogenesis ,Ribosomal protein s6 ,Cancer research ,KRAS ,DNA Damage - 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 rpS6P−/− mice). Strikingly, the development of pancreatic cancer precursor lesions induced by either DMBA or mutant Kras was greatly reduced in rpS6P−/− 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. Cancer Res; 73(6); 1811–20. ©2012 AACR.
- Published
- 2013