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Phospholipase D2 downregulation induces cellular senescence through a reactive oxygen species-p53-p21Cip1/WAF1

Young-Hoon Lee1, Young-Seuk Bae1

  • 1School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Republic of Korea.

FEBS Letters
|July 28, 2014
PubMed

Insights

Phospholipase D2 (PLD2) downregulation triggers cellular senescence by increasing reactive oxygen species (ROS) via the p53-p21 pathway. This process is linked to protein kinase CK2 activity.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cellular senescence is a state of irreversible growth arrest.
  • Phospholipase D (PLD) enzymes, including PLD1 and PLD2, play roles in various cellular processes.
  • The precise mechanisms linking PLD2 to senescence are not fully understood.

Purpose of the Study:

  • To investigate the role of PLD1 and PLD2 in cellular senescence.
  • To elucidate the molecular pathways involved in PLD2-mediated senescence.

Main Methods:

  • Quantitative analysis of PLD1 and PLD2 mRNA expression during senescence.
  • Gene knockdown experiments using siRNA targeting PLD2 in IMR-90 and HCT116 cells.
  • Assessment of senescence markers, intracellular reactive oxygen species (ROS) levels, and p53/p21(Cip1/WAF1) pathway activation.
  • Investigating the role of NADPH oxidase and protein kinase CK2 (CK2).

Main Results:

  • PLD1 and PLD2 expression decreased transcriptionally during replicative and premature senescence.
  • PLD2 knockdown induced senescence in proliferating cells, dependent on p53 and p21(Cip1/WAF1).
  • PLD2 knockdown elevated intracellular ROS, which was mitigated by antioxidants and NADPH oxidase inhibition.
  • Elevated CK2α expression suppressed PLD2 downregulation-induced senescence, while PLD2 overexpression increased CK2 activity.

Conclusions:

  • PLD2 downregulation is a key driver of cellular senescence.
  • Senescence induced by PLD2 loss occurs through the p53-p21(Cip1/WAF1) pathway.
  • Increased ROS production, potentially mediated by CK2 inhibition, is central to PLD2-dependent senescence.
Keywords:
Phospholipase D2Protein kinase CK2Reactive oxygen speciesSenescencep21(Cip1/WAF1)p53

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