AJOU Central Library Repository: Engineering of "E3 ubiquitin ligase recruiting ligand fused to cytosol-penetrating antibody" to degrade cytosolic β-catenin

Engineering of "E3 ubiquitin ligase recruiting ligand fused to cytosol-penetrating antibody" to degrade cytosolic β-catenin

Alternative Abstract: Oncogenic protein degradation approach has emerged as a new concept to overcome the limitation of classical monoclonal antibody therapy. Some researches on cytosolic protein degradation using small molecule or polypeptides has been conducted, but not complete IgG-format. Here, for the first time, I report eliminating cytosolic β-catenin using cytosol-penetrating antibody in human IgG1 format. I engineered β-catenin specific antibody (inBC) with improved anti-tumor activity by fusion with E3 ubiquitin ligase, termed inBC-E3. I found that inBC-VHL recruits Cul2 E3 complex in the proximity of the neo-substrate β-catenin, thus entering to ubiquitin proteasome pathway for degradation. inBC-VHL exhibits tumor growth inhibition in vitro and in vivo according to β-catenin depletion by conferring β-catenin degradation activity to inBC, which had no tumor suppressive effect. My results identified that engagement of ubiquitination cascade to the cancer-related protein for degradation offers potent therapeutic effects over traditional drug development strategies.

Appears in Collections:: Graduate School of Ajou University > Department of Molecular Science and Technology > 3. Theses(Master)

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