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701.
Discovery of 2,3,5-trisubstituted pyridine derivatives as potent Akt1 and Akt2 dual inhibitors 总被引:3,自引:0,他引:3
Zhao Z Leister WH Robinson RG Barnett SF Defeo-Jones D Jones RE Hartman GD Huff JR Huber HE Duggan ME Lindsley CW 《Bioorganic & medicinal chemistry letters》2005,15(4):905-909
This letter describes the discovery of a novel series of dual Akt1/Akt2 kinase inhibitors, based on a 2,3,5-trisubstituted pyridine scaffold. Compounds from this series, which contain a 5-tetrazolyl moiety, exhibit more potent inhibition of Akt2 than Akt1. 相似文献
702.
Davies BA Topp JD Sfeir AJ Katzmann DJ Carney DS Tall GG Friedberg AS Deng L Chen Z Horazdovsky BF 《The Journal of biological chemistry》2003,278(22):19826-19833
Rab5 GTPases are key regulators of protein trafficking through the early stages of the endocytic pathway. The yeast Rab5 ortholog Vps21p is activated by its guanine nucleotide exchange factor Vps9p. Here we show that Vps9p binds ubiquitin and that the CUE domain is necessary and sufficient for this interaction. Vps9p ubiquitin binding is required for efficient endocytosis of Ste3p but not for the delivery of the biosynthetic cargo carboxypeptidase Y to the vacuole. In addition, Vps9p is itself monoubiquitylated. Ubiquitylation is dependent on a functional CUE domain and Rsp5p, an E3 ligase that participates in cell surface receptor endocytosis. These findings define a new ubiquitin binding domain and implicate ubiquitin as a modulator of Vps9p function in the endocytic pathway. 相似文献
703.
Chen CC Ghole M Majumder A Wang Z Chandana S Wu HY 《The Journal of biological chemistry》2003,278(39):38094-38103
704.
Maruo T Matsuo H Shimomura Y Kurachi O Gao Z Nakago S Yamada T Chen W Wang J 《Steroids》2003,68(10-13):817-824
It is now evident that the use of levonorgestrel-releasing intrauterine system (LNg-IUS) is effective for long-term management of menorrhagic women with uterine myomas because of a striking reduction in menorrhagia. This prompted us to characterize the effects of progesterone (P4) on the growth and apoptosis of uterine leiomyoma cells. On the other hand, we have recently noted that epidermal growth factor (EGF) and IGF-I play a crucial role in prompting uterine leiomyoma growth through stimulating the proliferative potential and inhibiting apoptosis of cultured human leiomyoma cells. In the present review, attention was paid to evaluate the effects of P4 on the expression of growth factors (EGF, IGF-I) and apoptosis-related factors (TNFalpha, Bcl-2 protein) in cultured uterine leiomyoma cells. Treatment with P4 augmented EGF and Bcl-2 protein expression, but inhibited IGF-I and TNFalpha expression in cultured leiomyoma cells. It is known that TNFalpha induces apoptosis in a variety of cell types and Bcl-2 protein is an apoptosis-inhibiting gene product. Thus, the results obtained suggest that P4 has dual actions on uterine leiomyoma growth: one is to stimulate leiomyoma cell growth and survival through up-regulating EGF and Bcl-2 protein expression as well as down-regulating TNFalpha expression in those cells, and the other is to inhibit leiomyoma cell growth through down-regulating IGF-I expression in those cells. This may explain why the size of uterine myomas during use of LNg-IUS increases in some but decreases in other instances. This may also explain why the size of uterine myomas during pregnancy does not increase despite the overwhelming increase in circulating concentrations of sex steroid hormones. 相似文献
705.
Ontogeny of somatic embryos of grapevine (Vitis vinifera) produced from solid- and liquid-culture-derived proembryogenic masses (PEM) was compared using light and scanning electron microscopy. Somatic embryos produced from solid-medium-derived PEM (SPEM) had large cotyledons, little or no visible suspensor structure, and a relatively undeveloped concave shoot apical meristem, whereas those from liquid-medium-derived PEM (LPEM) had smaller cotyledons, a distinct suspensor, and a flat-to-convex shoot apical meristem. The convex shoot apical meristem in LPEM-derived somatic embryos formed as early as the heart stage of development; it was 4-6 cell layers deep and rich in protein. Suspensors persisted in fully developed and mature LPEM-derived somatic embryos. The SPEM-derived somatic embryos exhibited dormancy, as do mature zygotic embryos, which also have a rudimentary suspensor, whereas LPEM-derived embryos were not dormant. We hypothesize that the presence of a persistent suspensor in LPEM-derived somatic embryos modulates development, ultimately resulting in rapid germination and a high plant-regeneration rate. 相似文献
706.
707.
Elucidation of the c-Jun N-terminal kinase pathway mediated by Estein-Barr virus-encoded latent membrane protein 1 总被引:8,自引:0,他引:8
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Wan J Sun L Mendoza JW Chui YL Huang DP Chen ZJ Suzuki N Suzuki S Yeh WC Akira S Matsumoto K Liu ZG Wu Z 《Molecular and cellular biology》2004,24(1):192-199
Epstein-Barr virus (EBV) is associated with several human diseases including infectious mononucleosis and nasopharyngeal carcinoma. EBV-encoded latent membrane protein 1 (LMP1) is oncogenic and indispensable for cellular transformation caused by EBV. Expression of LMP1 in host cells constitutively activates both the c-Jun N-terminal kinase (JNK) and NF-kappaB pathways, which contributes to the oncogenic effect of LMP1. However, the underlying signaling mechanisms are not very well understood. Based mainly on overexpression studies with various dominant-negative constructs, LMP1 was generally thought to functionally mimic members of the tumor necrosis factor (TNF) receptor superfamily in signaling. In contrast to the prevailing paradigm, using embryonic fibroblasts from different knockout mice and the small interfering RNA technique, we find that the LMP1-mediated JNK pathway is distinct from those mediated by either TNF-alpha or interleukin-1. Moreover, we have further elucidated the LMP1-mediated JNK pathway by demonstrating that LMP1 selectively utilizes TNF receptor-associated factor 6, TAK1/TAB1, and c-Jun N-terminal kinase kinases 1 and 2 to activate JNK. 相似文献
708.
Jiqun S Xiuling X Zhijian C Wanhong L Yingliang W Shunyi Z Xianchun Z Dahe J Xin M Hui L Wenxin L Teng W 《Journal of biochemical and molecular toxicology》2004,18(4):187-195
Scorpion venom contains many small polypeptide toxins, which can modulate Na(+), K(+), Cl(-), and Ca(2+) ion-channel conductance in the cell membrane. A full-length cDNA sequence encoding a novel type of K(+)-channel toxin (named BmTxKS4) was first isolated and identified from a venom gland cDNA library of Buthus martensii Karsch (BmK). The encoded precursor contains 78 amino acid residues including a putative signal peptide of 21 residues, propeptide of 11 residues, and a mature peptide of 43 residues with three disulfide bridges. BmTxKS4 shares the identical organization of disulfide bridges with all the other short-chain K(+)-channel scorpion toxins. By PCR amplification of the genomic region encoding BmTxKS4, it was shown that BmTxKS4 composed of two exons is disrupted by an intron of 87 bp inserted between the first and the second codes of Phe (F) in the encoding signal peptide region, which is completely identical with that of the characterized scorpion K(+)-channel ligands in the size, position, consensus junctions, putative branch point, and A+T content. The GST-BmTxKS4 fusion protein was successfully expressed in BL21 (DE3) and purified with affinity chromatography. About 2.5 mg purified recombinant BmTxKS4 (rBmTxKS4) protein was obtained by treating GST-BmTxKS4 with enterokinase and sephadex chromatography from 1 L bacterial culture. The electrophysiological activity of 1.0 microM rBmTxKS4 was measured and compared by whole cell patch-clamp technique. The results indicated that rBmTxKS4 reversibly inhibited the transient outward K(+) current (I(to)), delayed inward rectifier K(+) current (I(k1)), and prolonged the action potential duration of ventricular myocyte, but it has no effect on the action potential amplitude. Taken together, BmTxKS4 is a novel subfamily member of short-strain K(+)-channel scorpion toxin. 相似文献
709.
目的:在老年人群中,小细胞肺癌的治疗难度大,缺乏有临床指导意义的研究数据,本文旨在通过对老年广泛期小细胞肺癌患者预后因素的分析寻找适合老年患者的化疗策略.方法:回顾性分析106例老年广泛期小细胞肺癌患者资料,应用SPSS13.0统计软件对数据进行单因素及COX回归多因素分析,探讨年龄、PS评分、化疗周期、化疗方案、血液学毒性等因素对生存的影响.结果:①单因素分析显示PS评分、化疗与否、化疗周期数、血液学毒性等因素对预后有影响,单药化疗与联合用药预后无明显差别.②COX回归多因素分析显示PS评分(P<0.001)、化疗周期数(P=0.002)是影响预后的因素.③单药化疗的血液学毒性明显低于联合用药,化疗周期数更多.结论:老年广泛期小细胞肺癌患者可从化疗中受益,四周期以上的化疗可明显延长生存时间,对于PS评分较差的患者,单药化疗可能是一个好的选择. 相似文献
710.
Abstract: A new family, Sinoalidae Wang and Szwedo fam. nov., is described from the Middle Jurassic Daohugou Biota (Inner Mongolia, China). Two new genera with three new species (Sinoala parallelivena Wang and Szwedo gen. et sp. nov., Jiania crebra Wang and Szwedo gen. et sp. nov., and Jiania gracila Wang and Szwedo sp. nov.) are erected based on well‐preserved whole‐bodied specimens. The morphological characters of Procercopidae and the new family are given, and a key to the species of Sinoalidae is presented. The genera Luanpingia Hong, 1983 and Huabeicercopis Hong, 1983 are revised and attributed to Sinoalidae. The genera Mesocercopis Hong, 1983 and Sinotettegarcta Hong, 1986 are considered junior synonyms of Anthoscytina Hong, 1983. Taxa assigned to Sinoalidae fam. nov. cannot be attributed to any previously known family, but share some general (plesiomorphic) characters with ancient Clypeata, for example, postclypeus distinctly swollen, transversely wrinkled, antenna with a flagellum of a few elongate segments, frons with median ocellus and lateral ocelli on crown. Moreover, the new family is closely related to Procercopidae (Cercopoidea) based on a pronotum with a median incision at the hind margin; tegmen slender, partly punctuate, basal portion of Sc not exceeding apex of basal cell, and hind legs with lateral spines. It has a mixture of ancestral characters shared with Hylicelloidea and Jurassic Procercopidae and some derived characters. Therefore, it is tentatively placed in Cercopoidea. A preliminary phylogram of Clypeata is presented based on the combination of fossil and morphological data. 相似文献