Involvement of an SCFSlmb complex in timely elimination of E2F upon initiation of DNA replication in Drosophila.
Involvement of an SCFSlmb complex in timely elimination of E2F upon initiation of DNA replication in Drosophila.
复制标题
在果蝇中启动DNA复制后，SCFSLMB复合物及时消除E2F。
DOI：
10.1186/1471-2156-4-9
复制
发表时间：
2003-06-04
期刊：
影响因子：
2.9
通讯作者：
O'Farrell, PH
中科院分区：
文献类型：
--
作者：
Hériché, JK;Ang, D;Bier, E;O'Farrell, PH
Cul 1是进化上保守的SCF型泛素连接酶的核心组分，其靶向特定的蛋白质进行破坏。SCF作用有助于细胞周期进程，但其作用的关键靶点很少被确定。我们发现，小鼠Cul 1（mCul 1）在幼虫翅盘的表达具有显性负效应。它减少，但不消除，SCF复合物的功能，促进Cubitus interruptus（SCF作用的目标）的积累，触发细胞凋亡，并导致小翅膀表型。对显性修饰该表型的突变的筛选显示出对E2 F功能降低的有效抑制，表明E2 F的下调受损有助于该表型。Cul 1的部分失活延迟了E2 F免疫荧光的突然丧失，超过了S期开始时下调的正常点。额外的筛选显示，轻度降低F-box编码基因slimb的功能增强了mCul 1过表达表型。在slim功能严重降低的slim突变细胞中，E2 F水平的细胞周期调节几乎不存在。这暗示Slimb，SCF的一个已知的靶向亚基，在E2 F下调。此外，Slimb和E2 F在体外以磷酸化依赖的方式相互作用。我们已经使用遗传和物理相互作用来鉴定G1/S转录因子E2 F作为果蝇中的SCFSlmb靶标。这些结果表明，SCFSlmb泛素连接酶在S期指导E2 F破坏。
Cul1 is a core component of the evolutionarily conserved SCF-type ubiquitin ligases that target specific proteins for destruction. SCF action contributes to cell cycle progression but few of the key targets of its action have been identified. We found that expression of the mouse Cul1 (mCul1) in the larval wing disc has a dominant negative effect. It reduces, but does not eliminate, the function of SCF complexes, promotes accumulation of Cubitus interruptus (a target of SCF action), triggers apoptosis, and causes a small wing phenotype. A screen for mutations that dominantly modify this phenotype showed effective suppression upon reduction of E2F function, suggesting that compromised downregulation of E2F contributes to the phenotype. Partial inactivation of Cul1 delayed the abrupt loss of E2F immunofluorescence beyond its normal point of downregulation at the onset of S phase. Additional screens showed that mild reduction in function of the F-box encoding gene slimb enhanced the mCul1 overexpression phenotype. Cell cycle modulation of E2F levels is virtually absent in slimb mutant cells in which slimb function is severely reduced. This implicates Slimb, a known targeting subunit of SCF, in E2F downregulation. In addition, Slimb and E2F interacted in vitro in a phosphorylation-dependent manner. We have used genetic and physical interactions to identify the G1/S transcription factor E2F as an SCFSlmb target in Drosophila. These results argue that the SCFSlmb ubiquitin ligase directs E2F destruction in S phase.
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