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NIAM-deficient mice are predisposed to the development of proliferative lesions including B-cell lymphomas
Journal article   Open access   Peer reviewed

NIAM-deficient mice are predisposed to the development of proliferative lesions including B-cell lymphomas

Sara M Reed, Jussara Hagen, Viviane P Muniz, Timothy R Rosean, Nick Borcherding, Sebastian Sciegienka, J Adam Goeken, Paul W Naumann, Weizhou Zhang, Van S Tompkins, …
PloS one, Vol.9(11), pp.e112126-e112126
2014
DOI: 10.1371/journal.pone.0112126
PMCID: PMC4231569
PMID: 25393878
url
https://doi.org/10.1371/journal.pone.0112126View
Published (Version of record) Open Access

Abstract

Nuclear Interactor of ARF and Mdm2 (NIAM, gene designation Tbrg1) is a largely unstudied inhibitor of cell proliferation that helps maintain chromosomal stability. It is a novel activator of the ARF-Mdm2-Tip60-p53 tumor suppressor pathway as well as other undefined pathways important for genome maintenance. To examine its predicted role as a tumor suppressor, we generated NIAM mutant (NIAM(m/m)) mice homozygous for a β-galactosidase expressing gene-trap cassette in the endogenous gene. The mutant mice expressed significantly lower levels of NIAM protein in tissues compared to wild-type animals. Fifty percent of aged NIAM deficient mice (14 to 21 months) developed proliferative lesions, including a uterine hemangioma, pulmonary papillary adenoma, and a Harderian gland adenoma. No age-matched wild-type or NIAM(+/m) heterozygous animals developed lesions. In the spleen, NIAM(m/m) mice had prominent white pulp expansion which correlated with enhanced increased reactive lymphoid hyperplasia and evidence of systemic inflammation. Notably, 17% of NIAM mutant mice had splenic white pulp features indicating early B-cell lymphoma. This correlated with selective expansion of marginal zone B cells in the spleens of younger, tumor-free NIAM-deficient mice. Unexpectedly, basal p53 expression and activity was largely unaffected by NIAM loss in isolated splenic B cells. In sum, NIAM down-regulation in vivo results in a significant predisposition to developing benign tumors or early stage cancers. These mice represent an outstanding platform for dissecting NIAM's role in tumorigenesis and various anti-cancer pathways, including p53 signaling.
 Cell Proliferation - genetics Genetic Predisposition to Disease Signal Transduction Adenoma - genetics Down-Regulation Humans Male Mice, Transgenic DNA-Binding Proteins - genetics Lymphoma, B-Cell - genetics Animals Hyperplasia - genetics Tumor Suppressor Protein p53 Cell Transformation, Neoplastic - genetics Female Mice Hemangioma - genetics

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