title: p21(WAF1) (/Cip1) limits senescence and acinar-to-ductal metaplasia formation during pancreatitis.
abstract: Trans-differentiation of pancreatic acinar cells into ductal-like lesions, a process defined as acinar-to-ductal metaplasia (ADM), is observed in the course of organ regeneration following pancreatitis. In addition, ADM is found in association with pre-malignant PanIN lesions and correlates with an increased risk of pancreatic adenocarcinoma (PDAC). Human PDAC samples show down-regulation of p21(WAF1) (/Cip1) , a key regulator of cell cycle and cell differentiation. Here we investigated whether p21 down-regulation is implicated in controlling the early events of acinar cell trans-differentiation and ADM formation. p21-mediated regulation of ADM formation and regression was analysed in vivo during the course of cerulein-induced pancreatitis, using wild-type (WT) and p21-deficient (p21(-/-) ) mice. Biochemical and immunohistochemical methods were used to evaluate disease progression over 2 weeks of the disease and during a recovery phase. We found that p21 was strongly up-regulated in WT acinar cells during pancreatitis, while it was absent in ADM areas, suggesting that p21 down-regulation is associated with ADM formation. In support of this hypothesis, p21(-/-) mice showed a significant increase in number and size of metaplasia. In addition, p21 over-expression in acinar cells reduced ADM formation in vitro, suggesting that the protein regulates the metaplastic transition in a cell-autonomous manner. p21(-/-) mice displayed increased expression and relocalization of β-catenin both during pancreatitis and in the subsequent recovery phase. Finally, loss of p21 was accompanied by increased DNA damage and development of senescence. Our findings are consistent with a gate-keeper role of p21 in acinar cells to limit senescence activation and ADM formation during pancreatic regeneration.
authors.affiliation: Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland.
authors.forename: Kamile
authors.initials: K
authors.lastname: Grabliauskaite
authors.forename: Adrian B
authors.initials: AB
authors.lastname: Hehl
authors.forename: Gitta M
authors.initials: GM
authors.lastname: Seleznik
authors.forename: Enrica
authors.initials: E
authors.lastname: Saponara
authors.forename: Kathryn
authors.initials: K
authors.lastname: Schlesinger
authors.forename: Richard A
authors.initials: RA
authors.lastname: Zuellig
authors.forename: Anja
authors.initials: A
authors.lastname: Dittmann
authors.forename: Martha
authors.initials: M
authors.lastname: Bain
authors.forename: Theresia
authors.initials: T
authors.lastname: Reding
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sonda
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology*; D002108:Ceruletide / Q000009:adverse effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D066298:In Vitro Techniques; D008679:Metaplasia; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000473:pathology* / Q000503:physiopathology*; D010195:Pancreatitis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D012038:Regeneration / Q000502:physiology; D051176:beta Catenin / Q000502:physiology
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051176:beta Catenin; D002108:Ceruletide
keywords: ADM; p21; pancreatitis; senescence; β-catenin