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PKCepsilon controls protection against TRAIL in erythroid progenitors
Prisco Mirandola1, Giuliana Gobbi, Cristina Ponti
1Department of Anatomy, Pharmacology, & Forensic Medicine, Human Anatomy Section, University of Parma, Ospedale Maggiore, Via Gramsci, 14, I-43100 Parma, Italy.
Blood
|September 17, 2005
Summary
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity in erythroid cells is regulated by protein kinase C epsilon (PKCepsilon). This kinase controls a specific "TRAIL window" during erythropoiesis, impacting cell numbers.
Area of Science:
- Hematopoiesis
- Cellular signaling
- Apoptosis
Background:
- Apoptosis regulates hematopoietic stem cell pool size and differentiation.
- TRAIL (TNF-related apoptosis-inducing ligand) modulates normal hematopoiesis.
- PKCepsilon's role in TRAIL response during erythropoiesis is investigated.
Purpose of the Study:
- To investigate if PKCepsilon acts as a switch for cellular response to TRAIL during erythropoiesis.
- To define the kinetics of TRAIL sensitivity in differentiating erythroid cells.
Main Methods:
- Analysis of TRAIL receptor expression on erythroid CD34 cells at different differentiation stages.
- Assessment of TRAIL-induced apoptosis in response to EPO (erythropoietin) stimulation.
- Evaluation of PKCepsilon and Bcl-2 expression levels during erythropoiesis.
Main Results:
- Erythroid CD34 cells are initially insensitive to TRAIL due to lack of receptor expression.
- Cells become sensitive to TRAIL from day 3, expressing death receptors.
- From day 7/8, EPO-induced PKCepsilon up-regulation confers TRAIL resistance, potentially via Bcl-2.
Conclusions:
- EPO orchestrates a time-restricted "TRAIL window" for negative regulation of erythroid cell numbers in human CD34 cells.
- PKCepsilon plays a critical role in limiting TRAIL sensitivity during later stages of erythroid differentiation.
- This regulated sensitivity ensures proper control over erythroid cell proliferation and survival.