HSP27 favors ubiquitination and proteasomal degradation of p27Kip1 and helps S-phase re-entry in stressed cells
HSP27 favors ubiquitination and proteasomal degradation of p27Kip1 and helps S-phase re-entry in stressed cells
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DOI：
10.1096/fj.05-4184fje
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发表时间：
2006-06-01
期刊：
影响因子：
4.8
通讯作者：
Garrido, Carmen
中科院分区：
文献类型：
--
作者：
Parcellier, Arnaud;Brunet, Mathilde;Garrido, Carmen
应激诱导的 HSP27 通过多种机制保护细胞免于死亡。我们最近证明HSP27还可以通过蛋白酶体途径增强一些蛋白质的降解。在这里，我们证明这些蛋白质之一是细胞周期蛋白依赖性激酶 (Cdk) 抑制剂 p27 (Kip1)。这种有利于细胞周期进展的蛋白质的泛素化和降解先前被证明涉及 Skp2 依赖性机制，即在 S-/G(2)-转变时，或 KPC（Kip1 泛素化促进复合物）依赖性机制，即在 G(0)/G(1) 转变时。在这项工作中，我们证明，响应血清耗竭，p27（Kip1）细胞含量首先增加，然后随着细胞开始死亡而逐渐减少。在这种应激条件下，HSP27 有利于 p27(Kip1) 被蛋白酶体泛素化和降解。针对 NO 供体三硝酸甘油酯 (GTN) 诱导的应激反应也进行了类似的观察。 HSP27 介导的 p27(Kip1) 泛素化不需要其在 Thr(187) 或 Ser-10 上的磷酸化，也不依赖于 SCFSkp2 泛素连接酶 E3 复合物。它促进 G(1)/S 转变，这表明在应激条件下，HSP27 可能使静止细胞有能力重新进入细胞周期。
Stress-inducible HSP27 protects cells from death through various mechanisms. We have recently demonstrated that HSP27 can also enhance the degradation of some proteins through the proteasomal pathway. Here, we show that one of these proteins is the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1). The ubiquitination and degradation of this protein that favors progression through the cell cycle was previously shown to involve either a Skp2-dependent mechanism, i.e., at the S-/G(2)-transition, or a KPC (Kip1 ubiquitination-promoting complex)-dependent mechanism, i.e., at the G(0)/G(1) transition. In this work, we demonstrate that, in response to serum depletion, p27(Kip1) cellular content first increases then progressively decreases as cells begin to die. In this stressful condition, HSP27 favors p27(Kip1) ubiquitination and degradation by the proteasome. A similar observation was made in response to stress induced by the NO donor glyceryl trinitrate (GTN). HSP27-mediated ubiquitination of p27(Kip1) does not require its phosphorylation on Thr(187) or Ser-10, nor does it depend on the SCFSkp2 ubiquitin ligase E3 complex. It facilitates the G(1)/S transition, which suggests that, in stressful conditions, HSP27 might render quiescent cells competent to re-enter the cell cycle.