Role of p21(WAF1/CIP1) as an attenuator of both proliferative and drug-induced apoptotic signals in BCR-ABL-transformed hematopoietic cells.
The constitutive tyrosine kinase activity of the BCR-ABL fusion protein plays a crucial role in the pathogenesis of chronic myeloid leukemia and promotes growth factor-independent survival of hematopoietic cells. In 32D cells, expression levels of retrovirally transduced BCR-ABL were positively correlated with the levels of the cell cycle regulator protein p21, and this upregulation of p21 expression depended on the kinase activity of BCR-ABL. To assess the role of p21 on BCR-ABL-positive hematopoietic cells, we compared proliferation and drug-induced apoptosis in bone marrow (BM) cells from wild-type and p21 knockout mice after retroviral transfer of the BCR-ABL fusion gene. As compared with wild-type cells, p21 knockout cells showed increased proliferation, suggesting that p21 acted as an attenuator of BCR-ABL-mediated cell proliferation. In marked contrast, deletion of p21 promoted apoptosis induction by imatinib and taxol in BCR-ABL-transformed BM cells. These findings demonstrate that p21 has a dual function in BCR-ABL-transformed murine BM cells: It attenuates the effects of two apparently opposed phenomena such as BCR-ABL-mediated cell proliferation and drug-induced apoptosis. This dual function of p21 calls for a cautious evaluation of the suitability of p21 as a secondary target in anticancer therapy.
Forster
Karin
K
Clinical Cooperation Group Gene Therapy, GSF-Research Center for Environment and Health, Marchioninistrasse 25, 81377, Munich, Germany.
Obermeier
Axel
A
Mitina
Olga
O
Simon
Nicola
N
Warmuth
Markus
M
Krause
Günter
G
Hallek
Michael
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl; D006412:Hematopoietic Stem Cells; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D017239:Paclitaxel / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012190:Retroviridae; D014161:Transduction, Genetic; D050257:Tubulin Modulators / Q000494:pharmacology*
D001549:Benzamides; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050257:Tubulin Modulators; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D017239:Paclitaxel