Faculty Collaboration Database

NIAM-deficient mice are predisposed to the development of proliferative lesions including B-cell lymphomas. PLoS One 2014;9(11):e112126

Date

11/14/2014

Pubmed ID

25393878

Pubmed Central ID

PMC4231569

DOI

10.1371/journal.pone.0112126

Scopus ID

2-s2.0-84911493985 (requires institutional sign-in at Scopus site)   7 Citations

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.

Author List

Reed SM, Hagen J, Muniz VP, Rosean TR, Borcherding N, Sciegienka S, Goeken JA, Naumann PW, Zhang W, Tompkins VS, Janz S, Meyerholz DK, Quelle DE

Author

Siegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenoma
Animals
Cell Proliferation
Cell Transformation, Neoplastic
DNA-Binding Proteins
Down-Regulation
Female
Genetic Predisposition to Disease
Hemangioma
Humans
Hyperplasia
Lymphoma, B-Cell
Male
Mice
Mice, Transgenic
Signal Transduction
Tumor Suppressor Protein p53