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Protein kinase D1 is essential for Ras-induced senescence and tumor suppression by regulating senescence-associated

Pan Wang1, Limin Han1, Hong Shen1

  • 1Peking University Research Center on Aging,Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;

Proceedings of the National Academy of Sciences of the United States of America
|May 16, 2014
PubMed

Insights

Protein kinase D1 (PKD1) is a key mediator of oncogene-induced senescence (OIS) and the senescence-associated secretory phenotype (SASP). This study reveals the ROS-PKCδ-PKD1 pathway is crucial for OIS and SASP, impacting tumor development.

Area of Science:

  • Cellular senescence
  • Oncogenesis
  • Signal transduction pathways

Background:

  • Oncogene-induced senescence (OIS) acts as a tumor suppressor mechanism.
  • Reactive oxygen species (ROS) are critical for OIS, but downstream signaling is unclear.
  • The senescence-associated secretory phenotype (SASP) is characteristic of senescent cells, with regulatory mechanisms largely unknown.

Purpose of the Study:

  • To identify downstream effectors of ROS signaling in oncogenic Ras-induced senescence (OIS).
  • To elucidate the mechanisms regulating the senescence-associated secretory phenotype (SASP).
  • To investigate the role of Protein Kinase D1 (PKD1) in OIS and SASP.

Main Methods:

  • Investigated the activation of PKD1 by oncogenic Ras expression.
  • Analyzed the role of PKD1 in mediating inflammatory cytokines (IL-6, IL-8) via NF-κB modulation.
  • Examined the ROS-protein kinase Cδ (PKCδ)-PKD1 axis in OIS and SASP establishment.
  • Assessed the consequences of PKD1 ablation on Ras OIS, cell transformation, and tumorigenesis.

Main Results:

  • Protein kinase D1 (PKD1) was identified as a downstream effector of ROS signaling in Ras-induced OIS.
  • PKD1 activation by oncogenic Ras promotes OIS and SASP by regulating IL-6 and IL-8 through NF-κB.
  • The ROS-PKCδ-PKD1 pathway is essential for IL-6/IL-8 induction and SASP maintenance.
  • Ablation of PKD1 bypassed Ras OIS, promoting cell transformation and tumorigenesis.

Conclusions:

  • PKD1 is a critical mediator of ROS signaling in oncogene-induced senescence (OIS).
  • The ROS-PKCδ-PKD1 pathway plays a vital role in regulating the senescence-associated secretory phenotype (SASP).
  • This pathway is a key determinant in preventing tumor development by promoting OIS and SASP.

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