Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Exocrine pancreatic disorders in transsgenic mice expressing human keratin 8
M. Llanos Casanova, … , Miguel Vidal, José L. Jorcano
M. Llanos Casanova, … , Miguel Vidal, José L. Jorcano
Published June 1, 1999
Citation Information: J Clin Invest. 1999;103(11):1587-1595. https://doi.org/10.1172/JCI5343.
View: Text | PDF
Article Article has an altmetric score of 3

Exocrine pancreatic disorders in transsgenic mice expressing human keratin 8

  • Text
  • PDF
Abstract

Keratins K8 and K18 are the major components of the intermediate-filament cytoskeleton of simple epithelia. Increased levels of these keratins have been correlated with various tumor cell characteristics, including progression to malignancy, invasive behavior, and drug sensitivity, although a role for K8/K18 in tumorigenesis has not yet been demonstrated. To examine the function of these keratins, we generated mice expressing the human K8 (hk8) gene, which leads to a moderate keratin-content increase in their simple epithelia. These mice displayed progressive exocrine pancreas alterations, including dysplasia and loss of acinar architecture, redifferentiation of acinar to ductal cells, inflammation, fibrosis, and substitution of exocrine by adipose tissue, as well as increased cell proliferation and apoptosis. Histological changes were not observed in other simple epithelia, such as the liver. Electron microscopy showed that transgenic acinar cells have keratins organized in abundant filament bundles dispersed throughout the cytoplasm, in contrast to control acinar cells, which have scarce and apically concentrated filaments. The phenotype found was very similar to that reported for transgenic mice expressing a dominant-negative mutant TGF-β type II receptor (TGFβRII mice). We show that these TGFβRII mutant mice also have elevated K8/K18 levels. These results indicate that simple epithelial keratins play a relevant role in the regulation of exocrine pancreas homeostasis and support the idea that disruption of mechanisms that normally regulate keratin expression in vivo could be related to inflammatory and neoplastic pancreatic disorders.

Authors

M. Llanos Casanova, Ana Bravo, Angel Ramírez, Gabriela Morreale de Escobar, Felipe Were, Glenn Merlino, Miguel Vidal, José L. Jorcano

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
Analysis of HK8 protein and mRNA in transgenic mouse pancreas. (a) Weste...
Analysis of HK8 protein and mRNA in transgenic mouse pancreas. (a) Western blot analysis of total protein extracts (10 μg) from pancreata of 6-week-old nontransgenic mice (Co), nonphenotypic transgenic mice (line TGK8-6), and phenotypic transgenic (line TGK8-4) mice. Triplicate gels were immunoblotted using anti-HK8 mAb M20 (top); rat mAb TROMA-1, which, under these conditions, recognizes mouse K8 strongly (double asterisk) and human K8 weakly (single asterisk) (middle); or the anti-K18 polyclonal antibody 1589 (bottom). (b) Northern blot analysis using 15 μg of total RNA from pancreata of 6-week-old animals bearing different hk8 transgene copy numbers. The filters were sequentially hybridized for HK8 (top), mK18 (middle), and 7S (bottom). (c) Coomassie blue–stained gel. Equal amounts of cytoskeletal extracts from the same amount (in grams) of pancreata and livers from 6-week-old control and transgenic mice were loaded. (d and e) Immunodetection of K8 in pancreas sections. Paraffin-embedded sections from 2-month-old control (d) and transgenic (e) pancreata. Control pancreas was stained with the TROMA-1 mAb to view endogenous mK8. The signal is restricted to the apical region of acinar cells and to ductal cells. Transgenic pancreas sections were labeled with the HK8-specific CAM 5.2 antibody. The staining is stronger and appears throughout the cytoplasm of acinar cells. The inset shows an area of ductules reacting with antibody CAM 5.2; the arrow depicts an acinus undergoing dedifferentiation into a tubular complex. L, islet of Langerhans. Scale bar: 60 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Referenced in 1 patents
29 readers on Mendeley
See more details