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The anticancer agent indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation. To delineate the precise mechanism by which indisulam mediates the DCAF15–RBM39 interaction, we solved the DCAF15–DDB1–DDA1–indisulam–RBM39(RRM2) complex structure to a resolution of 2.3 Å. DCAF15 has a distinct topology that embraces the RBM39(RRM2) domain largely via non-polar interactions, and indisulam binds between DCAF15 and RBM39(RRM2), coordinating additional interactions between the two proteins. Studies with RBM39 point mutants and indisulam analogs validated the structural model and defined the RBM39 α-helical degron motif. The degron is found only in RBM23 and RBM39, and only these proteins were detectably downregulated in indisulam-treated HCT116 cells. This work further explains how indisulam induces RBM39 degradation and defines the challenge of harnessing DCAF15 to degrade additional targets. The crystal and cryo-electron microscopy structure analysis of the DCAF15–DDB1–DDA1–indisulam–RBM39 complex revealed the detailed mechanism of action of indisulam-induced RBM39 degradation and defined an α-helical degron motif in RBM39.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Transferrin receptor (TfR) has been shown to be significantly overexpressed in different types of cancers. We discovered TfR as a target for gambogic acid (GA), used in traditional Chinese medicine and a previously undiscovered link between TfR and the rapid activation of apoptosis. The binding site of GA on TfR is independent of the transferrin binding site, and it appears that GA potentially inhibits TfR internalization. Down-regulation of TfR by RNA interference decreases sensitivity to GA-induced apoptosis, further supporting TfR as the primary GA receptor. In summary, GA binding to TfR induces a unique signal leading to rapid apoptosis of tumor cells. These results suggest that GA may provide an additional approach for targeting the TfR and its use in cancer therapy.

A novel Lewis acid-promoted allylation procedure based on the reaction of allyl(cyclopentadienyl)iron(II) dicarbonyl complex with aldehydes and ketones has been developed in which the iron group is retained within the adduct in the form of an isolable iron-olefin $\\pi$-complex. The zwitterionic iron-olefin $\\pi$-complex undergoes nucleophilic additions with primary alkoxides to give acyclic polyols or tetrahydrofuran derivatives, respectively. Depending on the reaction conditions, these additions can occur either intermolecularly or intramolecularly. When the iron-olefin $\\pi$-complex is treated with alkoxides (MeO$\\rm\\sp-,\\ BnO\\sp-,\\ CH\\sb2$=CHCH$\\rm\\sb2O\\sp-)$ in alcoholic solvents, the alkoxides are added regioselectively to the internal center of the double bond complex to give a $\\beta$-alkoxy alkyliron complex. However, if the iron-olefin $\\pi$-complex is treated with a base (K$\\rm\\sp+\\ \\sp{t}BuO\\sp-)$ in an aprotic solvent, a (3+2) iron-tetrahydrofuran-cycloadduct derivative is obtained. In either case, the alkyliron product can be converted to its carboxylic ester using ceric ammonium nitrate in methanol. Lewis acid catalysts can be used to promote the formal (3+2) -cycloaddition process. For aromatic aldehydes, the (3+2) -cycloaddition is best done using 15 mol% ZnCl$\\sb2$ in $\\rm CH\\sb2Cl\\sb2,$ while for ketones and aliphatic aldehydes, TiCl$\\sb4$ is the preferred Lewis acid. The ratio of trans:cis stereoisomers is about 1.1-3.1:1 depending on the nature and the amount of the Lewis acid used. A discussion of the mechanistic features of this cycloaddition process is presented. The (3+2) -cyclization process can be executed in intramolecular fashion to construct tricyclic fused furan rings in a single pot procedure. This strategy promises to offer a convenient and efficient method for assembling structurally complex, multi-cyclic rings commonly found in naturally-occurring compounds.

The anti-cancer agent Indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor leading to RBM39 ubiquitination and proteasome-mediated degradation. To delineate the precise mechanism by which Indisulam mediates DCAF15-RBM39 interaction, we solved the DCAF15-DDB1-DDA1-Indisulam-RBM39(RRM2) complex structure to 2.3 Angstroms. DCAF15 has a novel topology which embraces the RBM39(RRM2) domain largely via nonpolar interactions, and Indisulam binds between DCAF15 and RBM39(RRM2) and coordinates additional interactions between the two proteins. Studies with RBM39 point mutants and Indisulam analogs validated the structural model and defined the RBM39 alpha-helical degron motif. The degron is found only in RBM23 and RBM39 and only these proteins were detectably downregulated in Indisulam-treated HCT116 cells. This work further explains how Indisulam induces RBM39 degradation and defines the challenge of harnessing DCAF15 to degrade novel targets.

R2-03; 目的：观察电针对内脏高敏感大鼠结肠神经生长因子(nerve growth factor, NGF)和神经生长因子受体(nerve growth factor receptor, NGFR)表达的影响，探讨电针治疗慢性内脏高敏感性的作用机制。方法：将24只新生乳鼠随机分为正常组、模型组和电针组。参照 Al-Chaer 法制备内脏高敏感性大鼠模型。电针组予电针天枢、上巨虚治疗，每次20分钟，每天1次，连续7天。首次治疗后，通过观察大鼠腹壁撤回反射(abdominal withdrawal reflex, AWR)评分以评价内脏高敏感性大鼠的痛阈。治疗7天后，采集大鼠结肠组织进行NGF和NGFR免疫组织化学检测。结果：模型组大鼠的AWR评分均高于正常组，经电针治疗后均降低。模型组大鼠的结肠NGF和NGFR阳性表达较正常组显著增加(P＜0.05)，电针组治疗后NGF和NGFR阳性表达均显著降低(P＜0.001)。结论：电针可使内脏高敏感性大鼠的痛阈升高，并降低结肠的NGF和NGFR表达。电针对结肠NGF和NGFR表达的调节可能是其治疗慢性内脏高敏感性的外周作用机制之一。