Bcr-Abl upregulates cytosolic p21WAF-1/CIP-1 by a ...
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| Title | Bcr-Abl upregulates cytosolic p21WAF-1/CIP-1 by a phosphoinositide-3-kinase (PI3K)-independent pathway |
| Author(s) | K. Keeshan, T. Cotter, S. McKenna |
| Journal | British journal of haematology |
| Date | 2003 |
| Volume | 123 |
| Issue | 1 |
| Start page | 34 |
| End page | 44 |
| Abstract | Chronic myeloid leukaemia invariably progresses from a drug-sensitive to a drug-resistant, aggressive acute leukaemia. The mechanisms responsible for this are unknown, although loss of p53 has been reported in approximately 25% of cases. Elevated expression of Bcr-Abl is also associated with disease progression. We have shown that cells expressing high levels of Bcr-Abl also express elevated levels of p53 and the cell cycle inhibitor, p21WAF-1. Despite this, cells continue to cycle and are drug resistant. As p21WAF-1 inhibitory activity is associated with nuclear localization, we investigated its localization in Bcr-Abl-expressing cells, and found that it is predominantly cytoplasmic. We have also shown that it associates physically with the serine/threonine kinase AKT, but this association and the cytosolic location of p21WAF-1 are phosphinositide-3-kinase (PI3K) independent. Cytosolic p21WAF-1 has been reported to have a prosurvival role in other transformed cells. In Bcr-Abl-expressing cells, p21WAF-1 rapidly diminishes as the cells are sensitized to apoptosis, using the inhibitor STI571. It is possible therefore that p21WAF-1 could also have a positive, prosurvival role in these cells. This study suggests that, by retaining p21WAF-1 in a cytosolic location, Bcr-Abl can evade the cell cycle arrest normally induced by nuclear p21WAF-1 and therefore also enable the cells to negate an important feature of a tumour suppressor response. |
| ISSN | 0007-1048 |
Using APA 6th Edition citation style.
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