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Vol. 18, Issue 12, 4969-4978, December 2007

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Reg-II Is an Exocrine Pancreas Injury-Response Product That Is Up-Regulated by Keratin Absence or Mutation

Bihui Zhong^*,,,, Pavel Strnad^*,,, Diana M. Toivola^*,,||, Guo-Zhong Tao^*,, Xuhuai Ji^*,, Harry B. Greenberg^*,, and M. Bishr Omary^*,

*Department of Medicine, Palo Alto Veterans Affairs Medical Center, Palo Alto, CA 94304; Stanford University Digestive Disease Center, Stanford, CA 94305; Division of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China; and ^||Biosciences, Department of Biology, Abo Akademi University, FI-20520, Turku, Finland

Submitted February 27, 2007; Revised August 6, 2007; Accepted September 14, 2007
Monitoring Editor: Asma Nusrat

The major keratins in the pancreas and liver are keratins 8 and 18 (K8/K18), but their function seemingly differs in that liver K8/K18 are essential cytoprotective proteins, whereas pancreatic K8/K18 are dispensable. This functional dichotomy raises the hypothesis that K8-null pancreata may undergo compensatory cytoprotective gene expression. We tested this hypothesis by comparing the gene expression profile in pancreata of wild-type and K8-null mice. Most prominent among the up-regulated genes in K8-null pancreas was mRNA for regenerating islet-derived (Reg)-II, which was confirmed by quantitative reverse transcription-polymerase chain reaction and by an anti-Reg-II peptide antibody we generated. Both K8-null and wild-type mice express Reg-II predominantly in acinar cells as determined by in situ hybridization and immunostaining. Analysis of Reg-II expression in various keratin-related transgenic mouse models showed that its induction also occurs in response to keratin cytoplasmic filament collapse, absence, or ablation of K18 Ser52 but not Ser33 phosphorylation via Ser-to-Ala mutation, which represent situations associated with predisposition to liver but not pancreatic injury. In wild-type mice, Reg-II is markedly up-regulated in two established pancreatitis models in response to injury and during the recovery phase. Thus, Reg-II is a likely mouse exocrine pancreas cytoprotective candidate protein whose expression is regulated by keratin filament organization and phosphorylation.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

Address correspondence to: M. Bishr Omary (mbishr{at}stanford.edu).

Abbreviations used: Ab, antibody; CDD, choline-deficient diet; FDR, false discovery rate; H&E, hematoxylin and eosin; Hsp, heat-shock protein; h, human; IF, intermediate filament; ISH, in situ hybridization; K, keratin; Reg, regenerating islet-derived; SAM, significance analysis of microarray; WT, wild type.

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