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Jeong, Yuji,Kim, Taejoon,Kim, Suyeun,Hong, Yoon-Ki,Cho, Kyoung Sang,Lee, Im-Soon Elsevier 2018 Biochemical and biophysical research communication Vol.496 No.4
<P><B>Abstract</B></P> <P>The nuclear receptor-binding SET domain protein gene (<I>NSD</I>) family encodes a group of highly conserved SET domain-containing histone lysine methyltransferases that are important in multiple aspects of development in various organisms. The association of <I>NSD1</I> duplications has been reported with growth retardation diseases in humans. In this study, to gain insight into the molecular mechanisms by which the overexpression of <I>NSD1</I> influences the disease progression, we analyzed the gain-of-function mutant phenotypes of the <I>Drosophila NSD</I> using the <I>GAL4/UAS</I> system. Ubiquitous overexpression of <I>NSD</I> in the fly caused developmental delay and reduced body size at the larval stage, resulting in pupal lethality. Moreover, targeted overexpression in various developing tissues led to significant phenotype alterations, and the gain-of-function phenotypes were rescued by <I>NSD</I> RNAi knockdown. We also demonstrated that <I>NSD</I> overexpression not only enhanced the transcription of pro-apoptotic genes but also activated caspase. The atrophied phenotype of <I>NSD</I>-overexpressing wing was strongly suppressed by a loss-of-function mutation in <I>hemipterous</I>, which encodes a <I>Drosophila</I> Jun N-terminal kinase. Taken together, our findings suggest that NSD induces apoptosis via the activation of JNK, and thus contributes to the understanding of the molecular mechanisms involved in <I>NSD1</I>-related diseases in humans.</P> <P><B>Highlights</B></P> <P> <UL> <LI> NSD overexpression in <I>Drosophila</I> causes developmental delay and reduced body size. </LI> <LI> It resembles phenotypes of patients with <I>NSD1</I> duplication. </LI> <LI> NSD overexpression induces apoptosis in various imaginal discs of <I>Drosophila.</I> </LI> <LI> Apoptosis induced by NSD overexpression is suppressed by inhibiting the JNK pathway. </LI> </UL> </P>