Selective induction of mucin‐3 by hypoxia in intestinal epithelia
Abstract
Epithelial cells line mucosal surfaces (e.g., lung, intestine) and critically function as a semipermeable barrier to the outside world. Mucosal organs are highly vascular with extensive metabolic demands, and for this reason, are particularly susceptible to diminished blood flow and resultant tissue hypoxia. Here, we pursue the hypothesis that intestinal barrier function is regulated in a protective manner by hypoxia responsive genes. We demonstrate by PCR confirmation of microarray data and by avidin blotting of immunoprecipitated human Mucin 3 (MUC3), that surface MUC3 expression is induced in T84 intestinal epithelial cells following exposure to hypoxia. MUC3 RNA is minimally detectable while surface protein expression is absent under baseline normoxic conditions. There is a robust induction in both the mRNA (first evident by 8 h) and protein expression, first observed and maximally expressed following 24 h hypoxia. This is followed by a subsequent decline in protein expression, which remains well above baseline at 48 h of hypoxia. Further, we demonstrate that this induction of MUC3 protein is associated with a transient increase in the barrier restorative peptide, intestinal trefoil factor (ITF). ITF not only colocalizes with MUC3, by confocal microscopy, to the apical surface of T84 cells following exposure to hypoxia, but is also found, by co‐immunoprecipitation, to be physically associated with MUC3, following 24 h of hypoxia. In exploration of the mechanism of hypoxic regulation of mucin 3 expression, we demonstrated by luciferase assay that the full‐length promoter for mouse Mucin 3 (Muc3) is hypoxia‐responsive with a 5.08 ± 1.76‐fold induction following 24 h of hypoxia. Furthermore, analysis of both the human (MUC3A) and mouse (Muc3) promoters revealed potential HIF‐1 binding sites which were shown by chromatin immunoprecipitation to bind the pivotal hypoxia‐regulating transcription factor HIF‐1α. Taken together, these studies implicate the HIF‐1α mediated hypoxic induced expression of mucin 3 and associated ITF in the maintenance of intestinal barrier function under hypoxic conditions. J. Cell. Biochem. 99: 1616–1627, 2006. © 2006 Wiley‐Liss, Inc.
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HIF-dependent pathways are more to do with overall tissue integrity, ranging from increased mucin production, including molecules that modify mucins such as intestinal trefoil factor, to xenobiotic clearance by P-glycoprotein, to nucleotide metabolism (by ecto-5′-nucleotidase and CD73) and nucleotide signaling through the adenosine A2B receptor.
“Rather, the HIF-dependent pathways are more to do with overall tissue integrity, ranging from increased mucin production,31 including molecules that modify mucins, such as, intestinal trefoil factor4, to xenobiotic clearance by P-glycoprotein,20 to nucleotide metabolism (by ecto-5′-nucleotidase and CD73)21,22 and nucleotide signaling through the adenosine A2B receptor22.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [31]
HIF regulates the expression of a family of barrier protective factors including intestinal trefoil factor, the mucins and actin cytoskeletal crosslinkers.
“For example, HIF regulates the expression of a family of barrier protective factors including intestinal trefoil factor4, the mucins31 and actin cytoskeletal crosslinkers45.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [31]
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- Authors
- Louis, N. A., Hamilton, K. E., Canny, G., Shekels, L. L., Ho, S. B., & Colgan, S. P.
- Affiliations
- Brigham and Women's Hospital (US)
- University of Minnesota (US)
- Corresponding author
- Louis, Nancy A.
- Venue
- Journal of Cellular Biochemistry
- Publisher
- Wiley
- Published
- 2006-07-05
- Volume
- 99
- Issue
- 6
- Pages
- 1616-1627
- ISSN
- 0730-2312 (ISSN-L)
- 1097-4644
- OpenAlex
- W2085100595
- Cited by
- 144
- References
- 49
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 11 · 2022: 11 · 2021: 4 · 2020: 11 · 2019: 7 · 2018: 4 · 2017: 8 · 2016: 15 · 2015: 14 · 2014: 6 · 2013: 12 · 2012: 6
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cellular Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 62007, DK-50189)
- National Institute of Dental and Craniofacial Research (P50DE016191, DE 016191)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- hypoxia, intestinal barrier function, HIF-1α, TFF3, mucin gene expression, mucosal barrier
- MeSH terms
- Trefoil Factor-2, Base Sequence, Cell Line, Humans, Intestinal Mucosa, Mucins, Peptides, Protein Binding, RNA, Messenger, Cell Hypoxia, Polymerase Chain Reaction, DNA Primers, Hypoxia-Inducible Factor 1, alpha Subunit
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