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The Ste20-like kinase SLK promotes p53 transactivation and apoptosis

Andrey V Cybulsky1, Tomoko Takano, Julie Guillemette

  • 1Div. of Nephrology, Royal Victoria Hospital, 687 Pine Ave. West, Montreal, Quebec H3A1A1, Canada. andrey.cybulsky@mcgill.ca

American Journal of Physiology. Renal Physiology
|July 31, 2009
PubMed

Insights

The study reveals that SLK kinase promotes kidney injury recovery by activating p53. This activation enhances apoptosis following renal ischemia-reperfusion injury, highlighting a key molecular pathway.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Renal Pathophysiology

Background:

  • Germinal center kinase SLK (Scratch-like kinase) activity increases during kidney development and after renal ischemia-reperfusion injury.
  • SLK is known to promote apoptosis through pathways involving apoptosis signal-regulating kinase-1 and p38 mitogen-activated protein kinase.
  • The role of p53 in the SLK-mediated apoptotic pathway remains to be fully elucidated.

Purpose of the Study:

  • To investigate the role of p53 as a potential effector of SLK in the context of renal ischemia-reperfusion injury.
  • To determine if SLK influences p53 transactivation and phosphorylation.
  • To examine the impact of SLK-induced p53 activity on apoptosis.

Main Methods:

  • Assessed p53 transactivation using a luciferase reporter assay with a p53 cis-acting enhancer element in COS-1 cells and glomerular epithelial cells (GECs).
  • Induced in vitro ischemia-reperfusion injury in GECs via chemical anoxia and glucose reexposure.
  • Analyzed p53 phosphorylation at specific serine residues (S33, S315) and utilized p53 mutants to identify key phosphorylation sites. Inhibited c-Jun N-terminal kinase (JNK) and p53 transactivation using pifithrin-alpha.

Main Results:

  • Overexpression of SLK stimulated p53 transactivational activity in both COS-1 cells and GECs.
  • In vitro ischemia-reperfusion injury increased p53 reporter activity in GECs, an effect amplified by SLK overexpression.
  • SLK induced p53 phosphorylation at S33 and S315; only the double S33A+S315A mutation abolished SLK-induced p53 activity. JNK inhibition attenuated SLK-induced p53 activity.
  • SLK overexpression enhanced apoptosis during in vitro ischemia-reperfusion, while a dominant-negative SLK mutant reduced it. Pifithrin-alpha inhibited apoptosis.

Conclusions:

  • SLK induces p53 phosphorylation at S33 and S315, leading to enhanced p53 transactivation.
  • The SLK-p53 pathway, particularly involving JNK signaling, plays a critical role in promoting apoptosis following renal ischemia-reperfusion injury.
  • Targeting the SLK-p53 interaction may offer a therapeutic strategy for mitigating kidney injury.

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