title: Loss of p27Kip¹ promotes metaplasia in the pancreas via the regulation of Sox9 expression.
abstract: p27Kip1 (p27) is a negative regulator of proliferation and a tumor suppressor via the inhibition of cyclin-CDK activity in the nucleus. p27 is also involved in the regulation of other cellular processes, including transcription by acting as a transcriptional co-repressor. Loss of p27 expression is frequently observed in pancreatic adenocarcinomas in human and is associated with decreased patient survival. Similarly, in a mouse model of K-Ras-driven pancreatic cancer, loss of p27 accelerates tumor development and shortens survival, suggesting an important role for p27 in pancreatic tumorigenesis. Here, we sought to determine how p27 might contribute to early events leading to tumor development in the pancreas. We found that K-Ras activation in the pancreas causes p27 mislocalization at pre-neoplastic stages. Moreover, loss of p27 or expression of a mutant p27 that does not bind cyclin-CDKs causes the mislocalization of several acinar polarity markers associated with metaplasia and induces the nuclear expression of Sox9 and Pdx1 two transcription factors involved in acinar-to-ductal metaplasia. Finally, we found that p27 directly represses transcription of Sox9, but not that of Pdx1. Thus, our results suggest that K-Ras activation, the earliest known event in pancreatic carcinogenesis, may cause loss of nuclear p27 expression which results in derepression of Sox9, triggering reprogramming of acinar cells and metaplasia.
authors.affiliation: INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université de Toulouse, Toulouse, France.|CNRS ERL5294, Toulouse, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Jeannot
authors.affiliation: INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université de Toulouse, Toulouse, France.|CNRS ERL5294, Toulouse, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Callot
authors.affiliation: INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université de Toulouse, Toulouse, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Baer
authors.affiliation: INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université de Toulouse, Toulouse, France.|CNRS ERL5294, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Duquesnes
authors.affiliation: Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Guerra
authors.affiliation: INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université de Toulouse, Toulouse, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Guillermet-Guibert
authors.affiliation: Department of Cell Biology, Immunology and Neurosciences, University of Barcelona - IDIBAPS, Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Bachs
authors.affiliation: INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université de Toulouse, Toulouse, France.|CNRS ERL5294, Toulouse, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Besson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008679:Metaplasia; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology*; D055758:SOX9 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C436291:CDKN1B protein, human; C493961:Cdkn1b protein, mouse; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: CDK; cell cycle; p27Kip1; pancreas