Autophagic degradation of the inhibitory p53 isoform Δ133p53α as a regulatory mechanism for p53-mediated senescence.
Autophagic degradation of the inhibitory p53 isoform Δ133p53α as a regulatory mechanism for p53-mediated senescence.
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DOI：
10.1038/ncomms5706
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发表时间：
2014-08-21
影响因子：
16.6
通讯作者：
Harris CC
中科院分区：
文献类型：
--
作者：
Horikawa I;Fujita K;Jenkins LM;Hiyoshi Y;Mondal AM;Vojtesek B;Lane DP;Appella E;Harris CC
Δ133P53α是一种抑制全长P53的P53亚型，在复制性衰老过程中以一种不依赖于基因调控和蛋白酶体介导的降解的方式下调。在这里，我们证明了与全长p53不同，Δ133p53α在复制衰老过程中通过自噬降解。药物抑制自噬可恢复复制衰老成纤维细胞中Δ133P53α的表达水平，而不影响全长P53。SiRNA介导的前自噬蛋白(ATG5、ATG7和Beclin-1)的敲除也恢复了Δ133P53α的表达。伴侣相关的E3泛素连接酶STUB1与Δ133P53α相互作用，在复制性衰老时下调。在增殖的早期传代的成纤维细胞中，STUB1的siRNA敲除诱导Δ133P53α的自噬降解，从而诱导衰老。在复制衰老或STUB1基因敲除后，Δ133P53α被招募到自噬小体中，与其自噬降解一致。这项研究揭示了STUB1是Δ133P53α降解和衰老的内源性调节因子，并发现了一种协调P53介导的衰老的P53异构体特异性蛋白质周转机制。
Δ133p53α, a p53 isoform that can inhibit full-length p53, is downregulated at replicative senescence in a manner independent of mRNA regulation and proteasome-mediated degradation. Here we demonstrate that, unlike full-length p53, Δ133p53α is degraded by autophagy during replicative senescence. Pharmacological inhibition of autophagy restores Δ133p53α expression levels in replicatively senescent fibroblasts, without affecting full-length p53. The siRNA-mediated knockdown of pro-autophagic proteins (ATG5, ATG7 and Beclin-1) also restores Δ133p53α expression. The chaperone-associated E3 ubiquitin ligase STUB1, which is known to regulate autophagy, interacts with Δ133p53α and is downregulated at replicative senescence. The siRNA knockdown of STUB1 in proliferating, early-passage fibroblasts induces the autophagic degradation of Δ133p53α and thereby induces senescence. Upon replicative senescence or STUB1 knockdown, Δ133p53α is recruited to autophagosomes, consistent with its autophagic degradation. This study reveals that STUB1 is an endogenous regulator of Δ133p53α degradation and senescence, and identifies a p53 isoform-specific protein turnover mechanism that orchestrates p53-mediated senescence.
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影响因子：
13.3
作者：
Finn, Patrick E.;Mesires, Nicholas T.;Dice, J. Fred
通讯作者：
Dice, J. Fred
影响因子：
21.3
作者：
Fujita, Kaori;Horikawa, Izumi;Mondal, Abdul M.;Jenkins, Lisa M. Miller;Appella, Ettore;Vojtesek, Borivoj;Bourdon, Jean-Christophe;Lane, David P.;Harris, Curtis C.
通讯作者：
Harris, Curtis C.
影响因子：
64.8
作者：
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通讯作者：
Gorgoulis, Vassilis G.
影响因子：
3.5
作者：
Kelemen O;Convertini P;Zhang Z;Wen Y;Shen M;Falaleeva M;Stamm S
通讯作者：
Stamm S
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J