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

Abed Khalaileh, Avigail Dreazen, Areej Khatib, Roy Apel, Avital Swisa, Norma Kidess-Bassir, Anirban Maitra, Oded Meyuhas, Yuval Dor, Gideon Zamir

פרסום מחקרי: פרסום בכתב עתמאמרביקורת עמיתים

תקציר

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), anmTOReffector 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.

שפה מקוריתאנגלית אמריקאית
עמודים (מ-עד)1811-1820
מספר עמודים10
כתב עתCancer Research
כרך73
מספר גיליון6
מזהי עצם דיגיטלי (DOIs)
סטטוס פרסוםפורסם - 15 מרץ 2013

ASJC Scopus subject areas

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  • ???subjectarea.asjc.1300.1306???

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