Document Detail

Activation of protein kinase C relays distinct signaling pathways in the same cell type: differentiation and caspase-mediated apoptosis.
MedLine Citation:
PMID:  11042674     Owner:  NLM     Status:  MEDLINE    
Activation of PKC with 5 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) for 72 h in human U937 myeloid leukemia cells is associated with induction of adherence, followed by monocytic differentiation and G0/G1 cell cycle arrest. In this study, we demonstrate that in addition to these effects about 25% of U937 cells accumulated in an apoptotic subG1 phase after TPA treatment. The appearance of these apoptotic suspension cells was detectable throughout the time course of the culture and was independent of TPA concentrations between 0.5 and 500 nM. Experiments with cells synchronized by centrifugal elutriation revealed dominant susceptibility of G1-phase cells to TPA-mediated apoptosis. While adherent cells expressed differentiation markers including the integrin CD11c, this effect was less pronounced in the TPA-treated suspension fraction. Moreover, previous work has demonstrated cell cycle arrest in differentiating U937 cells. Accordingly, PKC activation by TPA treatment was associated with a significant expression of the cdk/cyclin inhibitor p21WAF/CIP/sdi-1 in the adherent population and subsequent G0/G1 cell cycle arrest. In contrast, suspension cells failed to induce significant levels of p21WAF/CIP/sdi-1 after TPA stimulation. Immunoblotting experiments demonstrated no difference in the expression of the pro-apoptotic factors Bax, Bad, and Bak in either control U937 and TPA-treated adherent or suspension cells, respectively. However, anti-apoptotic factors including Bcl-2, Bcl-xL, and Mcl-1 were significantly induced in the adherent population whereas no induction was detectable in the suspension cells. In this context, incubation with the caspase-3/caspase-7 specific tetrapeptide inhibitor DEVD prior to TPA treatment prevented an accumulation of cells in subG1, respectively, demonstrating an involvement of these caspases. Taken together, these data suggest that PKC activation can relay distinct signaling pathways such as induction of adherence coupled with monocytic differentiation and growth arrest, or induction of caspase-mediated apoptosis coupled with the failure to adhere and to differentiate.
G Meinhardt; J Roth; R Hass
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cell death and differentiation     Volume:  7     ISSN:  1350-9047     ISO Abbreviation:  Cell Death Differ.     Publication Date:  2000 Sep 
Date Detail:
Created Date:  2000-11-02     Completed Date:  2000-11-14     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  9437445     Medline TA:  Cell Death Differ     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  795-803     Citation Subset:  IM    
Medizinische Klinik Innenstadt, Department of Hematology/Oncology, Ludwig-Maximilians-University, Ziemssenstrasse 1, 80336 Munich, Germany.
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MeSH Terms
Annexin A5 / metabolism
Antigens, CD18 / metabolism
Caspases / antagonists & inhibitors,  metabolism*
Cell Adhesion
Cell Differentiation*
Cyclin-Dependent Kinase Inhibitor p21
Cyclins / antagonists & inhibitors,  metabolism
Enzyme Activation
Flow Cytometry
G1 Phase / drug effects
Protein Kinase C / metabolism*
Signal Transduction*
Tetradecanoylphorbol Acetate / pharmacology*
Time Factors
U937 Cells
Reg. No./Substance:
0/Annexin A5; 0/Antigens, CD18; 0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 16561-29-8/Tetradecanoylphorbol Acetate; EC Kinase C; EC 3.4.22.-/Caspases

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