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Lee, Keon ,Yong,Jang, Gun ,Hyuk,Byun, Cho ,Hyun,Jeun, Minhong,Searson, Peter ,C.,Lee, Kwan ,Hyi Portland Press Ltd. 2017 Bioscience reports Vol.37 No.3
<P>Preclinical screening with animal models is an important initial step in clinical translation of new drug delivery systems. However, establishing efficacy, biodistribution, and biotoxicity of complex, multicomponent systems in small animal models can be expensive and time-consuming. Zebrafish models represent an alternative for preclinical studies for nanoscale drug delivery systems. These models allow easy optical imaging, large sample size, and organ-specific studies, and hence an increasing number of preclinical studies are employing zebrafish models. In this review, we introduce various models and discuss recent studies of nanoscale drug delivery systems in zebrafish models. Also in the end, we proposed a guideline for the preclinical trials to accelerate the progress in this field.</P>
Yeast SREBP Cleavage Activation Requires the Golgi Dsc E3 Ligase Complex
Stewart, Emerson ,V.,Nwosu, Christine ,C.,Tong, Zongtian,Roguev, Assen,Cummins, Timothy ,D.,Kim, Dong-Uk,Hayles, Jacqueline,Park, Han-Oh,Hoe, Kwang-Lae,Powell, David ,W.,Krogan, Nevan& Elsevier 2011 Molecular cell Vol.42 No.2
<P><B>Summary</B></P><P>Mammalian lipid homeostasis requires proteolytic activation of membrane-bound sterol regulatory element binding protein (SREBP) transcription factors through sequential action of the Golgi Site-1 and Site-2 proteases. Here we report that while SREBP function is conserved in fungi, fission yeast employs a different mechanism for SREBP cleavage. Using genetics and biochemistry, we identified four genes <I>d</I>efective for <I>S</I>REBP <I>c</I>leavage, <I>dsc1-4</I>, encoding components of a transmembrane Golgi E3 ligase complex with structural homology to the Hrd1 E3 ligase complex involved in endoplasmic reticulum-associated degradation. The Dsc complex binds SREBP and cleavage requires components of the ubiquitin-proteasome pathway: the E2-conjugating enzyme Ubc4, the Dsc1 RING E3 ligase, and the proteasome. <I>dsc</I> mutants display conserved aggravating genetic interactions with components of the multivesicular body pathway in fission yeast and budding yeast, which lacks SREBP. Together, these data suggest that the Golgi Dsc E3 ligase complex functions in a post-ER pathway for protein degradation.</P> <P><B>Graphical Abstract</B></P><P><ce:figure id='dfig1'></ce:figure></P><P><B>Highlights</B></P><P>► Yeast SREBP is proteolytically activated by a different mechanism than mammalian SREBP ► Deletion collection screen identified four <I>dsc</I> genes required for fission yeast SREBP cleavage ► Dsc proteins form a Golgi E3 ligase complex that resembles Hrd1 E3 ligase in ERAD ► Yeast SREBP cleavage requires activities of the ubiquitin-proteasome pathway</P>
SFPQ, a multifunctional nuclear protein, regulates the transcription of <i>PDE3A</i>
Rhee, Dong ,Keun,Hockman, Steven ,C.,Choi, Sunkyung,Kim, Yong-Eun,Park, Chungoo,Manganiello, Vincent ,C.,Kim, Kee ,K. Portland Press Ltd. 2017 Bioscience reports Vol.37 No.4
<P>Phosphodiesterase 3A (PDE3A), a member of the cGMP-inhibited cyclic nucleotide phosphodiesterase (PDE) family, plays important roles in oocyte maturation and vascular smooth muscle cell proliferation. However, the molecular mechanisms that regulate <I>PDE3A</I> gene expression remain largely unknown. In the present study, we investigated the transcriptional regulation of <I>PDE3A</I>, and found that the splicing factor proline- and glutamine-rich (SFPQ) protein modulated <I>PDE3A</I> mRNA levels. Multiple transcription start sites (TSS1, 2, and 3) were identified within the first exon of <I>PDE3A</I> using 5′-rapid amplification of cDNA ends (RACE). Variable expression levels of three <I>PDE3A</I> variants were also observed in human tissues and HeLa cells. Several putative SFPQ-binding sites were identified upstream of the regulatory region of <I>PDE3A</I>-TSSs using ChIP sequencing (ChIP-seq). Serum-induced <I>PDE3A</I> expression was affected by increasing the amount of SFPQ binding to the upstream regulatory region of <I>PDE3A</I>. In addition, transcription of <I>PDE3A</I> was lower in human cervical adenocarcinoma cells compared with normal cervical tissue. Furthermore, overexpression of <I>PDE3A</I> induced sensitivity to anticancer therapeutic agent, 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (DNMDP), in HeLa cells. Taken together, these results suggest that SFPQ functions as a transcriptional activator of <I>PDE3A</I>, which is involved in the regulation of DNMDP sensitivity, offering a novel molecular target for the development of anticancer therapies.</P>
Cá,mara, Yolanda,Asin-Cayuela, Jorge,Park, Chan ,Bae,Metodiev, Metodi ,D.,Shi, Yonghong,Ruzzenente, Benedetta,Kukat, Christian,Habermann, Bianca,Wibom, Rolf,Hultenby, Kjell,Franz, Thomas Elsevier 2011 Cell metabolism Vol.13 No.5
<P><B>Summary</B></P><P>Precise control of mitochondrial DNA gene expression is critical for regulation of oxidative phosphorylation capacity in mammals. The MTERF protein family plays a key role in this process, and its members have been implicated in regulation of transcription initiation and site-specific transcription termination. We now demonstrate that a member of this family, MTERF4, directly controls mitochondrial ribosomal biogenesis and translation. MTERF4 forms a stoichiometric complex with the ribosomal RNA methyltransferase NSUN4 and is necessary for recruitment of this factor to the large ribosomal subunit. Loss of MTERF4 leads to defective ribosomal assembly and a drastic reduction in translation. Our results thus show that MTERF4 is an important regulator of translation in mammalian mitochondria.</P> <P><B>Highlights</B></P><P>► Loss of MTERF4 leads to abolished mitochondrial translation ► MTERF4 forms a complex with the rRNA methyltransferase NSUN4 ► MTERF4 targets NSUN4 to the mitochondrial large ribosomal subunit</P>