Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia
Abstract
Background & aims The nonsteroidal anti-inflammatory drug-activated gene (NAG-1) was identified as a proapoptotic, antitumorigenic protein in vitro, induced by many antitumorigenic and chemopreventive drugs including cyclooxygenase inhibitors. However, its antitumorigenic activity has not been elucidated in vivo.Methods Transgenic mice were generated that ubiquitously overexpress human NAG-1 under the control of a chicken beta-actin promoter (CAG). The NAG-1 transgenic mice (NAG-(Tg+)) were characterized, and then the antitumorigenic activity was evaluated with 2 colorectal carcinogenesis models: chemical induction with azoxymethane and genetic induction using the Apc(Min+) mutation.Results NAG-(Tg+) showed no apparent phenotype other than a reduction in body weight, particularly in males. To examine whether NAG-1 expression would suppress intestinal tumorigenesis, the NAG-(Tg+) mice were treated with the colorectal carcinogen azoxymethane. NAG-(Tg+) mice developed 50% fewer aberrant crypt foci and no tumors, in comparison with nontransgenic littermates. This result demonstrates that expression of this human protein in vivo can suppress chemically induced carcinogenesis in the colon. The NAG-(Tg+) mice were also crossed with Apc(Min+) mice to determine the effect of the transgene on intestinal polyp formation. NAG-(Tg+) mice heterozygous for the Apc(Min+) mutation had a significantly reduced polyp load (60%) compared with nontransgenic Apc(Min+) littermates.Conclusions Our results support NAG-1 as an important regulator of intestinal adenoma growth in vivo and suggest that NAG-1 may act as a tumor suppressor gene.
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Overexpressing GDF-15 decreases body weight, fat mass and food intake, and improves glucose tolerance in mouse models.
“On the contrary, overexpressing GDF-15 led to decreased body weight, fat mass and food intake, improving the glucose tolerance in mouse models (83, 108–110).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [109]
Expression of human GDF15 improves glucose tolerance and insulin sensitivity, lowers body weight and leptin levels, and increases oxidative metabolism and energy expenditure in mice.
“The expression of human GDF15 (hGDF15) improved glucose tolerance and insulin sensitivity, lowered body weight and leptin levels, and increased oxidative metabolism and energy expenditure in mice [207,208] (Figure 2).”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [207]
Two studies found GDF15 transgenic mice were protected against obesity and had increased insulin sensitivity and energy expenditure without changes in food consumption compared to control mice.
“Two studies found that GDF15 transgenic mice were protected against obesity and had increased insulin sensitivity and energy expenditure without any changes in food consumption compared to control mice [207,208].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [207]
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- Authors
- Baek, S. J., Okazaki, R., Lee, S.-H., Martinez, J., Kim, J.-S., Yamaguchi, K., Mishina, Y., Martin, D. W., Shoieb, A., Mcentee, M. F., & Eling, T. E.
- Affiliations
- University of Tennessee at Knoxville (US)
- National Institute of Environmental Health Sciences (US)
- National Institutes of Health (US)
- Emory University (US)
- Corresponding author
- Eling, Thomas E.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2006-11
- Volume
- 131
- Issue
- 5
- Pages
- 1553-1560
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2115206585
- Cited by
- 175
- References
- 51
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 6 · 2023: 5 · 2022: 11 · 2021: 14 · 2020: 18 · 2019: 9 · 2018: 8 · 2017: 7 · 2016: 4 · 2015: 10 · 2014: 12 · 2013: 8 · 2012: 9
- FWCI
- 5.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (N02-CB-07008)
- National Institute of Environmental Health Sciences (K22ES011657)
- National Center for Research Resources (K26RR016645)
- Topics
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- NAG-1, tumor suppressor, colorectal carcinogenesis, intestinal tumors, azoxymethane, ApcMin/+ mice, aberrant crypt foci, intestinal polyps, adenoma, transgenic mice, apoptosis
- MeSH terms
- Animals, Female, Humans, Intestinal Neoplasms, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Phenotype, Genes, Tumor Suppressor, Cytokines, Genes, APC, Mice, Growth Differentiation Factor 15
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