Title | Control of Paneth Cell Fate, Intestinal Inflammation, and Tumorigenesis by PKCλ/ι. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Nakanishi Y, Reina-Campos M, Nakanishi N, Llado V, Elmen L, Peterson S, Campos A, De SK, Leitges M, Ikeuchi H, Pellecchia M, Blumberg RS, Diaz-Meco MT, Moscat J |
Journal | Cell Rep |
Volume | 16 |
Issue | 12 |
Pagination | 3297-3310 |
Date Published | 2016 09 20 |
ISSN | 2211-1247 |
Keywords | Animals, Cell Differentiation, Cell Transformation, Neoplastic, Colorectal Neoplasms, Crohn Disease, Humans, Inflammation, Intestinal Mucosa, Isoenzymes, Kaplan-Meier Estimate, Mice, Mice, Inbred C57BL, Paneth Cells, Protein Kinase C |
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. |
DOI | 10.1016/j.celrep.2016.08.054 |
Alternate Journal | Cell Rep |
PubMed ID | 27653691 |
PubMed Central ID | PMC5043519 |
Grant List | R01 DK108743 / DK / NIDDK NIH HHS / United States R37 DK044319 / DK / NIDDK NIH HHS / United States R01 CA192642 / CA / NCI NIH HHS / United States R01 DK088199 / DK / NIDDK NIH HHS / United States R01 CA168517 / CA / NCI NIH HHS / United States R01 CA172025 / CA / NCI NIH HHS / United States P30 CA030199 / CA / NCI NIH HHS / United States P30 DK034854 / DK / NIDDK NIH HHS / United States P01 CA081534 / CA / NCI NIH HHS / United States R01 DK044319 / DK / NIDDK NIH HHS / United States |
Related Lab:
Related Faculty:
Maria Diaz-Meco Conde, Ph.D.