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Mitotic Cdc6 Stabilizes Anaphase-Promoting Complex Substrates by a Partially Cdc28-Independent Mechanism, and This Stabilization Is Suppressed by Deletion of Cdc55

机译:有丝分裂的Cdc6通过部分独立于Cdc28的机制稳定后期促进复杂基质,并通过删除Cdc55来抑制这种稳定。

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摘要

Ectopic expression of Cdc6p results in mitotic delay, and this has been attributed to Cdc6p-mediated inhibition of Cdc28 protein kinase and failure to activate the anaphase-promoting complex (APC). Here we show that endogenous Cdc6p delays a specific subset of mitotic events and that Cdc28 inhibition is not sufficient to account for it. The depletion of Cdc6p in G2/M cells reveals that Cdc6p is rate limiting for the degradation of the APC/Cdc20 substrates Pds1p and Clb2p. Conversely, the premature expression of Cdc6p delays the degradation of APC/Cdc20 substrates. Abolishing Cdc6p/Cdc28p interaction does not eliminate the Cdc6-dependent delay of these anaphase events. To identify additional Cdc6-mediated, APC-inhibitory mechanisms, we looked for mutants that reversed the mitotic delay. The deletion of SWE1, RAD24, MAD2, or BUB2 had no effect. However, disrupting CDC55, a PP2A regulatory subunit, suppressed the Cdc6p-dependent delay of Pds1 and Clb2 destruction. A specific role for CDC55 was supported by demonstrating that the lethality of Cdc6 ectopic expression in a cdc16-264 mutant is suppressed by the deletion of CDC55, that endogenous Cdc6p coimmunoprecipitates with the Cdc55 and Tpd3 subunits of PP2A, that Cdc6p/Cdc55p/Tpd3 interaction occurs only during mitosis, and that Cdc6 affects PP2A-Cdc55 activity during anaphase. This demonstrates that the levels and timing of accumulation of Cdc6p in mitosis are appropriate for mediating the modulation of APC/Cdc20.
机译:Cdc6p的异位表达导致有丝分裂延迟,这归因于Cdc6p介导的Cdc28蛋白激酶抑制和未能激活后期促进复合物(APC)。在这里,我们显示内源性Cdc6p延迟了有丝分裂事件的特定子集,而Cdc28抑制作用不足以解决这一问题。 G2 / M细胞中Cdc6p的消耗表明,Cdc6p限制了APC / Cdc20底物Pds1p和Clb2p的降解。相反,Cdc6p的过早表达会延迟APC / Cdc20底物的降解。取消Cdc6p / Cdc28p交互作用并不能消除这些后期事件的Cdc6依赖延迟。为了确定其他Cdc6介导的APC抑制机制,我们寻找了能够逆转有丝分裂延迟的突变体。 SWE1,RAD24,MAD2或BUB2的删除无效。但是,破坏CDC55,一个PP2A调节亚基,抑制了Cds6p依赖的Pds1和Clb2破坏的延迟。通过证明CDC55的缺失抑制了cdc16-264突变体中Cdc6异位表达的致死性,CDC55发挥了特定作用,该内源性Cdc6p与PP2A的Cdc55和Tpd3亚基共免疫沉淀,即Cdc6p / Cdc55p / Tpd3相互作用仅在有丝分裂期间发生,并且Cdc6在后期影响PP2A-Cdc55活性。这表明有丝分裂中Cdc6p的积累水平和时机适合于介导APC / Cdc20的调节。

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