Loss of p27Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression
Metrics: PDF 646 views | HTML 661 views | ?
Pauline Jeannot1,2,3, Caroline Callot1,2,3, Romain Baer1,2, Nicolas Duquesnes1,2,3, Carmen Guerra4, Julie Guillermet-Guibert1,2, Oriol Bachs5 and Arnaud Besson1,2,3
1 INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France
2 Université de Toulouse, Toulouse, France
3 CNRS ERL5294, Toulouse, France
4 Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
5 Department of Cell Biology, Immunology and Neurosciences, University of Barcelona - IDIBAPS, Barcelona, Spain
Arnaud Besson, email:
Keywords: p27Kip1, cell cycle, CDK, pancreas
Received: August 08, 2015 Accepted: September 12, 2015 Published: September 21, 2015
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 reprogrammation of acinar cells and metaplasia.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.