In:
The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1_Supplement ( 2018-05-01), p. 178.6-178.6
Abstract:
Altered protein dosage by defects in single genes leads to haploinsufficiencies and monogenic disorders, but the impact of small changes in gene expression on multifactorial disease is unknown. Here we show that a persistent small (~1.5 fold) increase in expression of NOD1 (Nucleotide-binding oligomerization domain-containing protein 1), a key innate sensor of bacterial infection, precipitates a large physiological effect with dramatically altered cellular function associated with carcinogenesis. Inhibition of miR-15b and miR-16 microRNA function leads to a ~1.2–1.4 fold increase in NOD1 protein concentration, with even slightly greater increases leading to ligand-independent, switch-like NOD1 activation. miRNA regulation of NOD1 plays a crucial role in limiting the development of an inflammatory state is impaired in gastric cancer with a small increase in NOD1 being associated with greater early patient mortality. Overall, our data show that tight control of NOD1 expression by miRNA prevents this sensor from exceeding a physiological switching checkpoint that promotes persistent inflammation and lethal cancer progression, and reveal the impact of a single and modest cellular alteration on cancer. These findings also have broader implications for understanding how small expression changes caused by genetic variation impact development of complex diseases like autoimmunity and cancer.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.200.Supp.178.6
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2018
detail.hit.zdb_id:
1475085-5
detail.hit.zdb_id:
3056-9
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