Protein kinase D1 is essential for Ras-induced senescence and tumor suppression by regulating senescence-associated inflammation.
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.
Peking University Research Center on Aging,Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
Pan
P
Wang
Peking University Research Center on Aging,Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
Limin
L
Han
Peking University Research Center on Aging,Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
Hong
H
Shen
Peking University Research Center on Aging,Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
Pengfeng
P
Wang
Peking University Research Center on Aging,Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
Cuicui
C
Lv
Peking University Research Center on Aging,Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
Ganye
G
Zhao
Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing 100069, China; and.
Jing
J
Niu
Peking University Research Center on Aging,Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
Lixiang
L
Xue
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, E1354 BST, Pittsburgh, PA 15261.
Qiming Jane
QJ
Wang
Peking University Research Center on Aging,Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China; cjbiochem@bjmu.edu.cn ttj@bjmu.edu.
Tanjun
T
Tong
Peking University Research Center on Aging,Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China; cjbiochem@bjmu.edu.cn ttj@bjmu.edu.
Jun
J
Chen
D000818:Animals; D016922:Cellular Senescence / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D016688:Mice, Inbred NOD; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism*
D017931:DNA Primers; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C089212:protein kinase D; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D018631:ras Proteins