Protein kinase D1 is essential for Ras-induced senescence and tumor suppression by regulating senescence-associated inflammation
Protein kinase D1 is essential for Ras-induced senescence and tumor suppression by regulating senescence-associated inflammation
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蛋白激酶 D1 通过调节衰老相关炎症，对于 Ras 诱导的衰老和肿瘤抑制至关重要
DOI：
10.1073/pnas.1310972111
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发表时间：
2014-05
影响因子：
11.1
通讯作者：
Chen Jun
中科院分区：
文献类型：
--
作者：
Wang Pan;Han Limin;Shen Hong;Wang Pengfeng;Lv Cuicui;Zhao Ganye;Niu Jing;Xue Lixiang;Wang Qiming Jane;Tong Tanjun;Chen Jun
癌基因诱导的衰老（OIS）是癌症发展的初始屏障。活性氧（Reactive oxygen species， ROS）在致癌Ras - OIS中起着关键作用。衰老细胞产生衰老相关分泌表型（senescence associated secretory phenotype， SASP），在肿瘤抑制和组织修复中发挥重要作用。然而，SASP调控的机制尚不清楚。在本文中，我们发现ros -蛋白激酶Cδ (PKCδ)-蛋白激酶D1 （PKD1）轴通过调节NF-κB活性对SASP的诱导和维持至关重要。考虑到SASP和ROS在全身性衰老和年龄相关疾病中的关键作用，本文阐明的ROS- pkc δ- pkd1通路与SASP调控之间的联系可能为干预年龄相关炎症和疾病提供新的靶点。癌基因诱导的衰老（OIS）是肿瘤发展的初始障碍。活性氧（Reactive oxygen species， ROS）对致癌Ras OIS至关重要，但介导ROS信号的下游效应物仍相对难以捉摸。衰老细胞产生衰老相关的分泌表型（SASP）。然而，SASP调控的机制在很大程度上是未知的。在这里，我们发现蛋白激酶D1 （PKD1）是ROS信号的下游效应物，介导Ras OIS和SASP。PKD1被致癌Ras表达激活，PKD1通过调节NF-κB活性介导炎症细胞因子IL-6 （IL-6）和IL-8 （IL-8）促进Ras OIS。我们发现ros蛋白激酶Cδ (PKCδ)-PKD1轴对于IL-6/ il - 8诱导的建立和维持至关重要。此外，PKD1的消融导致Ras OIS旁路，促进细胞转化和肿瘤发生。总之，这些发现揭示了ROS-PKCδ-PKD1通路在Ras OIS和SASP调控中的作用。
Significance Oncogene-induced senescence (OIS) is an initial barrier for cancer development. Reactive oxygen species (ROS) play critical roles in oncogenic Ras OIS. Senescent cells develop a senescence-associated secretory phenotype (SASP), which has important role in tumor suppression and tissue repair. However, the mechanisms underlying the SASP regulation are not clear. In this paper, we show that ROS-protein kinase Cδ (PKCδ)-protein kinase D1 (PKD1) axis is essential for SASP induction and maintenance via modulation of NF-κB activity. Considering the pivotal role of both SASP and ROS in systemic aging and age-related diseases, the link between ROS-PKCδ-PKD1 pathway and SASP regulation elucidated here may provide a new target to intervene in age-related inflammation and diseases. Oncogene-induced senescence (OIS) is an initial barrier to tumor development. Reactive oxygen species (ROS) is critical for oncogenic Ras OIS, but the downstream effectors to mediate ROS signaling are still relatively elusive. Senescent cells develop a senescence-associated secretory phenotype (SASP). However, the mechanisms underlying the regulation of the SASP are largely unknown. Here, we identify protein kinase D1 (PKD1) as a downstream effector of ROS signaling to mediate Ras OIS and SASP. PKD1 is activated by oncogenic Ras expression and PKD1 promotes Ras OIS by mediating inflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8) via modulation of NF-κB activity. We demonstrate that ROS-protein kinase Cδ (PKCδ)-PKD1 axis is essential for the establishment and maintenance of IL-6/IL8 induction. In addition, ablation of PKD1 causes the bypass of Ras OIS, and promotes cell transformation and tumorigenesis. Together, these findings uncover a previously unidentified role of ROS-PKCδ-PKD1 pathway in Ras OIS and SASP regulation.
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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
DOI：
10.1152/physiol.00037.2010
发表时间：
2011-02
期刊：
Physiology (Bethesda, Md.)
影响因子：
--
作者：
Rozengurt E
通讯作者：
Rozengurt E
DOI：
10.1186/bcr2232
发表时间：
2009
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Eiseler T;Döppler H;Yan IK;Goodison S;Storz P
通讯作者：
Storz P
影响因子：
13.6
作者：
Freund A;Orjalo AV;Desprez PY;Campisi J
通讯作者：
Campisi J
蛋白激酶 D 信号传导在胰腺癌中的作用。
影响因子：
5.8
作者：
Guha, Sushovan;Tanasanvimon, Suebpong;Sinnett-Smith, James;Rozengurt, Enrique
通讯作者：
Rozengurt, Enrique