A proapoptotic function of p21 in differentiating granulocytes.
p21(waf 1/cip 1) (p21), best known for its ability to regulate the cell cycle, has been noted also to exert cell cycle-independent effects on apoptosis and differentiation. Inhibition of apoptosis by p21 has been reported in hematopoietic models, particularly in monocytes exposed to apoptogenic agents. The effect of p21 on survival has not hitherto been analyzed during the myeloblast to granulocyte transition. Using 32 Dc l3 murine myeloblasts, a cell line that proliferates in IL-3 and differentiates in G-CSF, we studied the effects of forced expression of p21 on cell survival. We hypothesized that exogenous p21 would suppress the modest levels of cell death associated with G-CSF-mediated differentiation of 32 Dc l3 cells. Contrary to expectations, we found that exogenous p21 enhanced apoptosis of cells removed from IL-3. The p21 overexpression led to decreased cell growth, caspase-3 activation and annexin positivity. These effects occurred only in the presence of G-CSF. These findings suggest that p21 is proapoptotic in granulopoiesis, and that this effect is masked by IL-3-mediated survival signals. Our results also indicate there are distinct and opposing effects of p21 on monocytic and granulocytic survival. Aberrantly high levels of p21 may contribute to disease processes involving excessive apoptosis of granulocyte precursors.
Ghanem
Louis
L
University of Pittsburgh School of Medicine, Department of Medicine, Hillman Cancer Center, Lab 2.18, 5117 Center Avenue, Pittsburgh, PA 15213, USA.
Steinman
Richard
R
D000818:Animals; D017302:Annexins / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000502:physiology
D017302:Annexins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007377:Interleukin-3; D016179:Granulocyte Colony-Stimulating Factor; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases