In mice, mutation of SMAD3 has been linked to colorectal adenocarcinoma, increased systemic inflammation, and accelerated wound healing. There is no conclusive evidence of similar activity in humans, however. A 2002 study investigated possible links between SMAD3 mutation and cancer of the pancreas and parathyroid gland, but found no connection. Increased SMAD3 activity has, however, been implicated in the pathogenesis of scleroderma. Smad3 is also a multifaceted regulator in adipose physiology and the pathogenesis of obesity and type 2 diabetes. Smad3-knockout mice have diminished adiposity, with improved glucose tolerance and insulin sensitivity. Despite their reduced physical activity arising from muscle atrophy, these Smad3-knockout mice are resistant to high-fat-diet induced obesity. Smad3-knockout mouse is a legitimate animal model of human aneurysms‐osteoarthritis syndrome(AOS), also named Loeys-Dietz Syndrome (type 3). Smad3 deficiency promotes inflammatory aortic aneurysms in angiotensin II-infused mice via the activation of iNOS. Macrophage depletion and inhibition of iNOS activity prevent aortic aneurysms related to Smad3 gene mutation. reference
The SMAD proteins are homologs of both the Drosophila protein "mothers against decapentaplegic" (MAD) and the C. elegans protein SMA. The name is a combination of the two. During Drosophila research, it was found that a mutation in the gene MAD in the mother repressed the gene decapentaplegic in the embryo. The phrase "Mothers against" was inspired by organizations formed by mothers to oppose social problems, such as Mothers Against Drunk Driving (MADD).
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