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The research group headed by Professor Masayuki Noguchi and Assistant Professor Futoshi Suizu of the Division of Cancer Biology of Hokkaido University’s Institute for Genetic Medicine has determined for the first time in the world that the excessive expression of a specific class of enzymes, or E3 ubiquitin ligase is possibly responsible for Down syndrome. Down syndrome, caused by a trisomy in chromosome 21, is a widely known genetic condition that causes definitive physical characteristics in facial features and stature, as well as various other health complications such as combined heart defects, leukemia, mental retardation, and early-onset Alzheimer’s disease. However, beyond these symptoms, the clinical pathology and the detailed molecular mechanisms detailing the condition have been unknown until recent breakthroughs in research. The research group looked into the relationships between the ligase tetratricopeptide repeat domain 3 (TTC3) and the development of clinical signs and pathological conditions using a molecular imaging technique (a biochemical approach) and cell strains from patients with Down syndrome. The results showed that when TTC3 on human chromosome 21 binds specifically to Akt (an important serine threonine kinase that determines the life or death of cells), cell proliferation and cell cycle control undergo a disturbance, which is related to the onset of the disease. The outcome of this study is expected to aid understanding of the onset of today’s most common genetic disorder and also lead to understanding the causes of common complications for Down syndrome patients such as Alzheimer’s disease (a serious problem for Japan’s graying population) and combined congenital heart defects. Website of the Division of Cancer Biology of Hokkaido University’s Institute for Genetic Medicine http://www.igm.hokudai.ac.jp/hu_ifgm_cb/eng/index.html  TTC3 is a novel E3 ubiquitin ligase for Akt In this study we demonstrated that TTC3 is a novel E3 ubiquitin ligase for Akt that preferentially binds to phosphorylated Akt, hence facilitating ubiquitination and proteasomal degradation within the nucleus. Since TTC3 is located within the DSCR (Down Syndrome Critical Region) of chromosome 21, the current study will provide not only the biological significances of the TTC3-Akt functional interaction, but also a new insight for the molecular mechanisms of DS, the most common genetic disorder in humans.
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