title: Control of Paneth Cell Fate, Intestinal Inflammation, and Tumorigenesis by PKCλ/ι.
abstract: Paneth cells are a highly specialized population of intestinal epithelial cells located in the crypt adjacent to Lgr5(+) stem cells, from which they differentiate through a process that requires downregulation of the Notch pathway. Their ability to store and release antimicrobial peptides protects the host from intestinal pathogens and controls intestinal inflammation. Here, we show that PKCλ/ι is required for Paneth cell differentiation at the level of Atoh1 and Gfi1, through the control of EZH2 stability by direct phosphorylation. The selective inactivation of PKCλ/ι in epithelial cells results in the loss of mature Paneth cells, increased apoptosis and inflammation, and enhanced tumorigenesis. Importantly, PKCλ/ι expression in human Paneth cells decreases with progression of Crohn's disease. Kaplan-Meier survival analysis of colorectal cancer (CRC) patients revealed that low PRKCI levels correlated with significantly worse patient survival rates. Therefore, PKCλ/ι is a negative regulator of intestinal inflammation and cancer through its role in Paneth cell homeostasis.
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakanishi
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Reina-Campos
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Naoko
authors.initials: N
authors.lastname: Nakanishi
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Llado
authors.affiliation: Bioinformatics and Structural Biology Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Elmen
authors.affiliation: Bioinformatics and Structural Biology Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Peterson
authors.affiliation: Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Campos
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Surya K
authors.initials: SK
authors.lastname: De
authors.affiliation: Biotechnology Centre of Oslo, University of Oslo, 0316 Oslo, Norway.
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.affiliation: Department of Surgery, Hyogo College of Medicine, Nishinomiya 663-8131, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ikeuchi
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.affiliation: Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: jmoscat@sbpdiscovery.org.
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D003424:Crohn Disease / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D019879:Paneth Cells / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism*; D000099293:Protein Kinase C-lambda
chemical_list: D007527:Isoenzymes; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda