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. We have observed that a persistent small 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. An approximately 1.1 to 1.2 fold increase in NOD1 protein concentration (~1.5 fold increase in NOD1 mRNA) leads to ligand-independent, switch-like NOD1 activation. Tight control of NOD1 expression plays a crucial role in limiting the development of an inflammatory state appears to be impaired in gastric adenocarcinoma with a small increase in NOD1 being associated with greater early patient mortality. In this proposal, we will investigate the regulatory circuit(s) that tightly control expression of NOD1 to prevent this sensor from exceeding a physiological switching checkpoint that promotes persistent inflammation and lethal cancer progression. We will conduct these investigations in the following specific aims: 1) To identify the mechanism(s) that control NOD1 expression and activation; 2) To understand if regulatory control of NOD1 is disrupted in gastric cancer patients and how a small increase in NOD1 expression promotes gastric cancer. Our investigations will reveal the impact of a single and modest cellular alteration on cancer, and will have broader implications for understanding how small expression changes caused by genetic variation impact development of complex diseases like autoimmunity and cancer.
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. We have found that very small increases in expression of NOD1, an innate sensor of bacterial infection, spontaneously lead to large- scale cancer-promoting gene activation, suggesting that NOD1 expression must be very tightly controlled in human cells. In this proposal, we will investigate the regulatory mechanisms that tightly control expression of NOD1 to prevent this sensor from exceeding a physiological switching checkpoint, and identify if loss of such regulatory control of NOD1 is responsible for lethal cancer progression in gastric cancer patients.
