A NOVEL F BOX PROTEIN REGULATING MITOSIS

描述(逐字摘自申请人的摘要)：积累 细胞周期蛋白B和细胞周期蛋白B/cdc2激酶的激活驱动有丝分裂。这个 有丝分裂激活的泛素连接酶泛素化细胞周期蛋白B 后期促进复合体(APC)，以及随后对细胞周期蛋白B的破坏 对有丝分裂的退出至关重要。一类独特的泛素连接酶，称为 干细胞因子复合体控制着许多细胞周期的转变，包括G1-S 以及G2-M转换。SCF复合体含有含有F-box基序的蛋白质。 这些F-box蛋白是允许SCF复合体结合的适配蛋白 泛素化目标。调查人员发现了一种新的F盒，名为 控制有丝分裂的进入和退出的SBP5。很像有丝分裂 周期蛋白，SBP5是有丝分裂进入所必需的，必须被破坏才能有丝分裂 出口。SBP5阻止有丝分裂退出的能力导致其靶向 APC的调节亚单位，称为CdC2O。SPB5在有丝分裂中被破坏，但 通过一种独立于APC的机制。SPB5也定位于有丝分裂的纺锤体。 他们怀疑与SBP5相关的泛素连接酶活性 有丝分裂纺锤体调节器的破坏。SBP5基因的过表达 导致中期停滞、纺锤体异常和细胞凋亡。目标 包括(1)SBP5的生化和突变研究；(2)确定 SBP5与有丝分裂纺锤体的相互作用；(3)An的体外研究 SBP5相关泛素连接酶活性；以及(4)人类同源物的研究 SBP5。通过将纺锤体控制与中期阻断和细胞凋亡偶联，SBP5 可能参与紫杉醇、长春花碱等微管毒物的途径 生物碱用来引发细胞死亡。了解SBP5如何阻止有丝分裂和 诱导细胞凋亡可能为创造新的癌症提供重要的见解 与长春新碱作用相似或协同的化疗药物 生物碱和紫杉醇。

DESCRIPTION (Verbatim from the applicant's abstract): The accumulation of cyclin B and activation of the cyclin B/Cdc2 kinase drives mitosis. The ubiquitination of cyclin B by a mitotically activated ubiquitin ligase, the Anaphase Promoting Complex (APC), and the subsequent destruction of cyclin B are critical for mitotic exit. A distinct class of ubiquitin ligases, called SCF complexes, control a number of cell cycle transitions, including the G 1-S and G2-M transitions. SCF complexes contain proteins that contain F-box motifs. These F-box proteins are adapter proteins that allow the SCF complexes to bind to ubiquitination targets. The investigator has discovered a new F-box called SBP5 that controls the entry into and exit from mitosis. Much like the mitotic cyclins, SBP5 is required for mitotic entry and must be destroyed for mitotic exit. The ability for SBP5 to block mitotic exit results from its targeting a regulatory subunit of the APC, called Cdc2O. SPB5 is destroyed in mitosis, but by an APC-independent mechanism. SPB5 also localizes to the mitotic spindle. They suspect that an SBP5-associated ubiquitin ligase activity mediates destruction of regulators of the mitotic spindle. Overexpression of SBP5 induces a metaphase arrest, spindle abnormalities, and apoptosis. The aims include (1) Biochemical and mutational studies of SBP5; (2) defining the interaction of SBP5 with the mitotic spindle; (3) in vitro studies of an SBP5-associated ubiquitin ligase activity; and (4) studies of a human homolog of SBP5. By coupling spindle control to a metaphase block and apoptosis, SBP5 may participate in the pathway that microtubule poisons like Taxol and vinca alkaloids use to trigger cell death. Understanding how SBP5 blocks mitosis and induces apoptosis may provide important insight for creating new cancer chemotherapeutic drugs that act similarly or synergistically with vinca alkaloids and Taxol.