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RISS 인기검색어
- 검색키워드
- 저자 : Mevius, Damiaan E.H.F. (검색결과 5 건)
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Recombinant Protein Expression and Purification of the Human HMTase MMSET/NSD2
Morishita, Masayo,Mevius, Damiaan,Shen, Yunpeng,Di Luccio, Eric Institute of Agricultural Science and Technology 2013 慶北大農學誌 Vol.31 No.3
Chromatin remodelers that include histone methyl transferases (HMTases) are becoming a focal point in cancer drug development. The NSD family of three HMTases, NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L are bona fide oncogenes found aberrantly expressed in several cancers, suggesting their potential role for novel therapeutic strategies. Several histone modifiers including HMTase have clear roles in human carcinogenesis but the extent of their functions and regulations are not well understood, especially in pathological conditions. The extents of the NSDs biological roles in normal and pathological conditions remain unclear. In particular, the substrate specificity of the NSDs remains unsettled and discrepant data has been reported. NSD2/MMSET is a focal point for therapeutic interventions against multiple myeloma and especially for t(4;14) myeloma, which is associated with a significantly worse prognosis than other biological subgroups. Multiple myeloma is the second most common hematological malignancy in the United States, after non-Hodgkin lymphoma. Herein, as a first step before entering a pipeline for protein x-ray crystallography, we cloned, recombinantly expressed and purified the catalytic SET domain of NSD2. Next, we demonstrated the catalytic activities, in vitro, of the recombinantly expressed NSD2-SET on H3K36 and H4K20, its biological targets at the chromatin.
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Recombinant Protein Expression and Purification of the Human HMTase MMSET/NSD2
Masayo Morishita,Damiaan Mevius,Yunpeng Shen,Eric di Luccio 경북대학교 농업생명과학대학 2013 Current Research on Agriculture and Life Sciences Vol.31 No.3
Chromatin remodelers that include histone methyl transferases (HMTases) are becoming a focal point in cancer drug development. The NSD family of three HMTases, NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L are bona fide oncogenes found aberrantly expressed in several cancers, suggesting their potential role for novel therapeutic strategies. Several histone modifiers including HMTase have clear roles in human carcinogenesis but the extent of their functions and regulations are not well understood, especially in pathological conditions. The extents of the NSDs biological roles in normal and pathological conditions remain unclear. In particular, the substrate specificity of the NSDs remains unsettled and discrepant data has been reported. NSD2/MMSET is a focal point for therapeutic interventions against multiple myeloma and especially for t(4;14) myeloma, which is associated with a significantly worse prognosis than other biological subgroups. Multiple myeloma is the second most common hematological malignancy in the United States, after non-Hodgkin lymphoma. Herein, as a first step before entering a pipeline for protein x-ray crystallography, we cloned, recombinantly expressed and purified the catalytic SET domain of NSD2. Next, we demonstrated the catalytic activities, in vitro, of the recombinantly expressed NSD2-SET on H3K36 and H4K20, its biological targets at the chromatin.
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Morishita, Masayo,Cho, Minju,Ryu, Juhee,Mevius, Damiaan E.H.F.,Di Luccio, Eric 경북대학교 농업과학기술연구소 2010 慶北大農學誌 Vol.28 No.-
The epigenetic therapy of cancers is emerging as an effective and valuable approach to both chemotherapy and the chemoprevention of cancer. The utilization of epigenetic targets that include histone methyltransferase (HMTase), Histone deacetylatase, and DNA methyltransferase, are emerging as key therapeutic targets. SET containing proteins such as the HMTase Setd1b has been found significantly amplified in cancerous cells. In order to shed some light on the histone methyl transferase family, we cloned the Setd1b gene from Mus musculus and build a collection of vectors for recombinant protein expression in E.coli that will pave the way for further structural biology studies. We prospect the role of the Setd1b pathway in cancer therapy and detail its unique value for designing novel anti-cancer epigenetic-drugs.
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Identification of LEM-14 inhibitor of the oncoprotein NSD2
Shen, Yunpeng,Morishita, Masayo,Lee, Doohyun,Kim, Shinae,Lee, Taeho,Mevius, Damiaan E.H.F.,Roh, Yeonjeong,di Luccio, Eric Elsevier 2019 Biochemical and biophysical research communication Vol.508 No.1
<P><B>Abstract</B></P> <P>The NSD family (NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1) are histone lysine methyltransferases (HMTases) essential for chromatin regulation. The NSDs are oncoproteins, drivers of a number of tumors and are considered important drug-targets but the lack of potent and selective inhibitors hampers further therapeutic development and limits exploration of their biology. In particular, MMSET/NSD2 selective inhibition is being pursued for therapeutic interventions against multiple myeloma (MM) cases, especially in multiple myeloma t(4;14)(p16.3;q32) translocation that is associated with a significantly worse prognosis than other MM subgroups. Multiple myeloma is the second most common hematological malignancy, after non-Hodgkin lymphoma and remains an incurable malignancy.</P> <P>Here we report the discovery of LEM-14, an NSD2 specific inhibitor with an <I>in vitro</I> IC<SUB>50</SUB> of 132 μM and that is inactive against the closely related NSD1 and NSD3. LEM-14-1189, a LEM-14 derivative, differentially inhibits the NSDs with <I>in vitro</I> IC<SUB>50</SUB> of 418 μM (NSD1), IC<SUB>50</SUB> of 111 μM (NSD2) and IC<SUB>50</SUB> of 60 μM (NSD3). We propose LEM-14 and derivative LEM-14-1189 as tools for studying the biology of the NSDs and constitute meaningful steps toward potent NSDs therapeutic inhibitors.</P> <P><B>Highlights</B></P> <P> <UL> <LI> NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1 are histone methyltransferases and oncoproteins. </LI> <LI> Inhibition of NSD2 in multiple myeloma t(4;14)(p16.3;q32) is urgently needed. </LI> <LI> We report the discovery of a NSD2 specific inhibitor and derivatives that differentially inhibits the NSDs. </LI> <LI> We investigate the molecular mechanism for NSD2 specific inhibition. </LI> <LI> We propose our inhibitors LEM-14 and LEM-14-1189 as tools for studying the biology of the NSDs and for drug-design. </LI> </UL> </P>
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