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유사분열 관련 효소 VRK1의 세포생물학 및 약리학적 조절

Title
유사분열 관련 효소 VRK1의 세포생물학 및 약리학적 조절
Authors
김완일
Date Issued
2013
Publisher
포항공과대학교
Abstract
VRK1 (vaccinia-related kinase 1) is one of the mitotic histone kinases and plays an important role in cell cycle regulation by phosphorylating residues Thr3 and Ser10 of histone H3. The VRK1-mediated phosphorylation of histone H3 is prominent at late G2 and M phase. VRK1-mediated phosphorylation of histone H3 should be restricted in mitosis for consistent cell cycling, and defects in this process trigger cellular catastrophe. However, an interphasic regulator against VRK1 has not been actually investigated so far. Here, I show that the histone variant macrodomain-containing histone H2A1.2 functions as a suppressor against VRK1 during interphase. The level of -iimacroH2A1.2 was markedly reduced in the mitotic phase, and the macroH2A1.2-mediated inhibition of histone H3 phosphorylation occurred mainly during interphase. I also found direct interaction and binding features between VRK1 and macroH2A1.2 by NMR spectroscopy. Hence, this finding might provide valuable insight into the underlying molecular mechanism regarding an epigenetic regulation of histone H3 during the cell cycle. Targeting specific molecules is a promising cancer treatment because certain types of cancer cells are dependent on specific oncogenes. This strategy led to the development of therapeutics that employ monoclonal antibodies or small molecule inhibitors. However, the continued development of novel molecular targeting inhibitors is required to target the various oncogenes associated with the diverse types and stages of cancer. Obtusilactone B is a butanolide derivative purified from Machilus thunbergii. Here, I show that obtusilactone B functions as a small molecule inhibitor, that causes abnormal nuclear envelope dynamics and inhibits growth by suppressing vaccinia-related kinase 1 (VRK1)-mediated phosphorylation of barrier-toautointegration factor (BAF). BAF is important in maintaining lamin-integrity, which is closely associated with diseases that include cancer. Specific binding of obtusilactone B to BAF suppressed VRK1-mediated BAF phosphorylation and the subsequent dissociation of the nuclear envelope from DNA that allows cells to progress through the cell cycle. Obtusilactone B potently induced tumor cell death in vitro, indicating that specific targeting of BAF to block cell cycle progression can be an effective anti-cancer strategy. This result demonstrates that targeting a major constituent of the nuclear envelope may be a novel and promising alternative approach to cancer treatment.
URI
http://postech.dcollection.net/jsp/common/DcLoOrgPer.jsp?sItemId=000001560818
http://oasis.postech.ac.kr/handle/2014.oak/1865
Article Type
Thesis
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