http://chineseinput.net/에서 pinyin(병음)방식으로 중국어를 변환할 수 있습니다.
변환된 중국어를 복사하여 사용하시면 됩니다.
Baicalein induces functional hypoxia-inducible factor-1alpha and angiogenesis.
Cho, Hyunju,Lee, Ho-Youl,Ahn, Dae-Ro,Kim, Sang Yoon,Kim, Sunyun,Lee, Keun Byeol,Lee, You Mie,Park, Hyunsung,Yang, Eun Gyeong American Society for Pharmacology and Experimental 2008 Molecular pharmacology Vol.74 No.1
<P>Targeting the oxygen-sensing mechanisms of the hypoxiainducible factor (HIF) pathway provides pharmacological ways of manipulating the HIF response. Because HIF-1alpha-specific prolyl-4 hydroxylases (PHDs) prime degradation of HIF-1alpha, we have made an effort to find a small molecule capable of up-regulating the HIF pathway by inhibiting prolyl hydroxylation. Through an in vitro high-throughput screen, we have discovered a PHD2 inhibitor baicalein, which is also found to abrogate asparaginyl hydroxylation of HIF-1alpha. Such inhibitory effects are reversed by the addition of excess 2-oxoglutarate and iron(II), suggesting the involvement of baicalein's binding at the enzyme active sites, which has also been corroborated by spectroscopic binding assays between baicalein and enzyme. In addition, baicalein suppresses ubiquitination of HIF-1alpha, which works in concert with the inhibition of the HIF-specific hydroxylases to increase the HIF-1alpha content, leading to induction of HIF-1-mediated reporter gene activity and target gene transcription in tissue culture cells, whereas it induces HIF-independent activation of other genes. Furthermore, in vivo organ models based on the chick chorioallantoic membrane assay demonstrate that baicalein promotes new blood vessel formation. Together, our results indicate that baicalein possesses a proangiogenic potential and thus might have the therapeutic utility in the treatment of ischemic diseases.</P>
Won, Minho,Ro, Hyunju,Park, Hae-Chul,Kim, Kyoon E.,Huh, Tae-Lin,Kim, Cheol-Hee,Rhee, Myungchull Wiley-Liss, Inc. 2006 Developmental dynamics Vol.235 No.3
<P>Evolutionarily well-conserved Ca<SUP>2+</SUP>/calmodulin-dependent protein kinase (CaMK) proteins are known for their role as Ca<SUP>2+</SUP> signaling mediators. 1G5 encodes a CaMK like protein, which belongs to a calmodulin (CaM) kinase gene family. Here, we report the isolation of zebrafish homologue of mammalian 1G5, which we named 1G5z. 1G5z is composed of three major domains: (1) an N-terminal serine/threonine kinase domain, (2) a central calmodulin-binding domain, and (3) a C-terminal alanine-rich domain, the 1G5z-specific domain. 1G5z shares 83∼84% homology with other vertebrate 1G5 proteins. Spatiotemporal expression studies found that 1G5z is expressed by means of zygotic transcription and appears in various neuronal tissues from the 20-somite stage. 1G5z transcripts are more regionalized in the brain and spinal cord at 24 hr postfertilization (hpf). At 35 hpf, 1G5z transcripts are exclusively present in the anterior trunk spinal cord as well as in the hindbrain, tegmentum, hypothalamus, and telencephalon. This expression pattern lasts until 48 hpf but ceases in the trunk. At 72 hpf, 1G5z is abundantly transcribed particularly in the specific region of the tectum and eye. We further observed that the number of 1G5z-positive cells is dramatically increased in the mindbomb mutant embryos but abolished in the trigeminal ganglion and caudal trunk sensory neuron of the neurogenin1 morphant at 24 hpf. In addition, bromodeoxyuridine staining further confirmed that the 1G5z-positive cells were postmitotic sensory and interneurons. Developmental Dynamics 235:835–842, 2006. © 2006 Wiley-Liss, Inc.</P>
Lnx2 ubiquitin ligase is essential for exocrine cell differentiation in the early zebrafish pancreas
Won, Minho,Ro, Hyunju,Dawid, Igor B. National Academy of Sciences 2015 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.112 No.40
<P><B>Significance</B></P><P>Pancreas differentiation is of interest as an example of organogenesis and for its medical implications. We report here that regulation of protein stability is a player in the differentiation of certain cell lineages in the early zebrafish pancreas. The related E3 ubiquitin ligases Ligand of Numb protein-X (Lnx)2a and Lnx2b affect differentiation of exocrine cells, apparently by destabilizing Numb in exocrine progenitor cells. Numb is an inhibitor of Notch, a key regulator of pancreatic development. We suggest that Lnx2a/b destabilize Numb to derepress Notch, allowing precursors to proliferate and support subsequent differentiation. This study also highlights the fact that detailed analysis of morpholino versus mutant phenotypes may be required for a full understanding of their relationship.</P><P>The gene encoding the E3 ubiquitin ligase Ligand of Numb protein-X (Lnx)2a is expressed in the ventral-anterior pancreatic bud of zebrafish embryos in addition to its expression in the brain. Knockdown of Lnx2a by using an exon 2/intron 2 splice morpholino resulted in specific inhibition of the differentiation of ventral bud derived exocrine cell types, with little effect on endocrine cell types. A frame shifting null mutation in <I>lnx2a</I> did not mimic this phenotype, but a mutation that removed the exon 2 splice donor site did. We found that Lnx2b functions in a redundant manner with its paralog Lnx2a. Inhibition of <I>lnx2a</I> exon 2/3 splicing causes exon 2 skipping and leads to the production of an N-truncated protein that acts as an interfering molecule. Thus, the phenotype characterized by inhibition of exocrine cell differentiation requires inactivation of both Lnx2a and Lnx2b. Human LNX1 is known to destabilize Numb, and we show that inhibition of Numb expression rescues the Lnx2a/b-deficient phenotype. Further, Lnx2a/b inhibition leads to a reduction in the number of Notch active cells in the pancreas. We suggest that Lnx2a/b function to fine tune the regulation of Notch through Numb in the differentiation of cell types in the early zebrafish pancreas. Further, the complex relationships among genotype, phenotype, and morpholino effect in this case may be instructive in the ongoing consideration of morpholino use.</P>
Myungchull Rhee,Hyunju Ro,장영주 한국분자세포생물학회 2004 Molecules and cells Vol.17 No.1
Siah is a mammalian homologue of Drosophila seven in absentia (sina) that is required for R7 photoreceptor development. Both the SINA and Siah family interact with ubiquitin-conjugating enzymes via an N-terminal RING domain and the C-terminal domain of SINA/ Siahs interacts with proteins targeted for degradation. Siah induces cell growth arrest by promoting -catenin degradation in a phosphorylation-independent manner as a result of indirect binding to -catenin. We previ-ously cloned a zebrafish homologue (Siaz) of Siah. Siaz shares high sequence homology with vertebrate Siah-2. We have now examined the role of Siaz in growth regulation using the trypan blue exclusion assay and flow cytometry and found that Siaz induces cellular growth arrest by inhibiting the G2/M transition. The C-terminal domain of Siaz that interacts with target proteins is not required for growth inhibition. We con-clude that the N-terminal RING and central domain of Siaz are sufficient to block the G2/M phase transition.
Lee, Seoghyun,Ro, Hyunju,In, Hyun Ju,Choi, Ji-Hee,Kim, Mun-Ock,Lee, Jinhyuk,Hong, Sung-Tae,Lee, Su Ui Elsevier 2018 Cytokine Vol.108 No.-
<P><B>Abstract</B></P> <P>Fisetin (3,7,3′,4′-tetrahydroxyflavone), a natural flavonoid, is a therapeutic agent for respiratory inflammatory diseases such as chronic obstructive pulmonary disease (COPD). However, detailed molecular mechanisms regarding the target protein of fisetin remain unknown.</P> <P>Fisetin significantly reduces tumour necrosis factor alpha (TNF-α)-induced interleukin (IL)-8 levels by inhibiting both nuclear factor kappa B (NF-κB) transcriptional activity and the phosphorylation of its upstream effectors. We show that fisetin prevents interactions between protein kinase C (PKC)δ and TNF receptor-associated factor 2 (TRAF2), thereby inhibiting the inhibitor of kappa B kinase (IKK)/NF-κB downstream signalling cascade. Furthermore, we found that fisetin directly binds to PKCδ <I>in vitro</I>. Our findings provide evidence that fisetin inhibits the TNF-α-activated IKK/NF-κB cascade by targeting PKCδ, thereby mediating inflammatory diseases such as COPD.</P> <P>These data suggest that fisetin is a good therapeutic drug for the treatment of inflammatory lung diseases, such as COPD, by inhibiting the TNF-α/NF-κB signalling pathway.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Fisetin inhibits TNF-α-increased <I>IL-8</I> gene expression by blocking NF-κB activity. </LI> <LI> Fisetin inhibits TNF-α-mediated interactions between PKCδ and TRAF2. </LI> <LI> Fisetin inhibits PKCδ activity. </LI> </UL> </P>