期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 21, 页码 7683-7688出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1310972111
关键词
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资金
- National Key Basic Research Program of China [2013CB530801, 2014CB910503]
- National Natural Science Foundation of China [81370455]
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-kappa B activity. We demonstrate that ROS-protein kinase C delta (PKC delta)-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-PKC delta-PKD1 pathway in Ras OIS and SASP regulation.
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