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

Autor:	Reed SM; 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., Hagen J; Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America., Muniz VP; 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., Rosean TR; Interdisciplinary Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America., Borcherding N; Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America., Sciegienka S; Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America., Goeken JA; Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America., Naumann PW; Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America., Zhang W; 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., Tompkins VS; Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America., Janz S; 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., Meyerholz DK; Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America., Quelle DE; 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.
Jazyk:	angličtina
Zdroj:	PloS one [PLoS One] 2014 Nov 13; Vol. 9 (11), pp. e112126. Date of Electronic Publication: 2014 Nov 13 (Print Publication: 2014).
DOI:	10.1371/journal.pone.0112126
Abstrakt:	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.
Databáze:	MEDLINE
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