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The Cell-Cycle Regulatory Protein p21CIP1/WAF1 Is Required for Cytolethal Distending Toxin (Cdt)-Induced Apoptosis
Bruce J Shenker1, Lisa M Walker1, Ali Zekavat1
1Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104, USA.
Pathogens (Basel, Switzerland)
|January 8, 2020
Summary
Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) induces apoptosis by increasing p21 levels. This study shows p21 is essential for Cdt-induced apoptosis and pro-apoptotic protein activation.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) causes cell-cycle arrest and apoptosis in lymphocytes.
- Toxicity is mediated by the CdtB subunit, which acts as a phosphatidylinositol (PI) 3,4,5-triphosphate (PIP3) phosphatase.
- The role of p21CIP1/WAF1 in Cdt-induced apoptosis is not fully understood.
Purpose of the Study:
- To investigate the role of p21CIP1/WAF1 in Cdt-induced apoptosis.
- To elucidate the mechanism by which Cdt regulates p21CIP1/WAF1 levels.
- To determine the downstream effects of p21CIP1/WAF1 modulation on apoptosis-related proteins.
Main Methods:
- Utilized lymphoid cell lines (Jurkat, MyLa) and primary human lymphocytes.
- Assessed p21CIP1/WAF1 levels and phosphorylation in response to Cdt.
- Employed a p21CIP1/WAF1 inhibitor (UC2288) and CRISPR/Cas9 gene editing to create p21CIP1/WAF1-deficient cells (Jurkatp21-).
- Quantified levels of pro-apoptotic proteins (Bid, Bax, Bak) and heat shock protein 90 (HSP90).
Main Results:
- Cdt induced p21CIP1/WAF1 increases dependent on CdtB's PIP3 phosphatase activity.
- UC2288 treatment and p21CIP1/WAF1 deficiency reduced Cdt-induced apoptosis.
- Cdt-induced upregulation of Bid, Bax, and Bak was p21CIP1/WAF1-dependent.
- p21CIP1/WAF1 increase was linked to elevated HSP90 levels and activity.
Conclusions:
- p21CIP1/WAF1 is a critical mediator of Cdt-induced apoptosis in lymphocytes.
- Cdt toxicity is significantly influenced by the regulation of p21CIP1/WAF1.
- HSP90 plays a role in the Cdt-mediated increase of p21CIP1/WAF1, contributing to apoptosis.
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