NIAM-deficient mice are predisposed to the development of proliferative lesions including B-cell lymphomas.
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.
Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America; Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, United States of America.
Sara M
SM
Reed
Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America.
Jussara
J
Hagen
Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America; Molecular and Cellular Biology Program, University of Iowa, Iowa City, Iowa, United States of America.
Viviane P
VP
Muniz
Interdisciplinary Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America.
Timothy R
TR
Rosean
Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America.
Nick
N
Borcherding
Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America.
Sebastian
S
Sciegienka
Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America.
J Adam
JA
Goeken
Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America.
Paul W
PW
Naumann
Interdisciplinary Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America; Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America.
Weizhou
W
Zhang
Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America.
Van S
VS
Tompkins
Interdisciplinary Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America; Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America.
Siegfried
S
Janz
Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America.
David K
DK
Meyerholz
Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America; Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, United States of America; Molecular and Cellular Biology Program, University of Iowa, Iowa City, Iowa, United States of America; Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America.
Dawn E
DE
Quelle
D000236:Adenoma / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation; D005260:Female; D020022:Genetic Predisposition to Disease; D006391:Hemangioma / Q000235:genetics; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53
D004268:DNA-Binding Proteins; C517540:Niam protein, mouse; D016159:Tumor Suppressor Protein p53