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Bcr‐Abl upregulates cytosolic p21 WAF‐1/CIP‐1 by a phosphoinositide‐3‐kinase (PI3K)‐independent pathway
Author(s) -
Keeshan Karen,
Cotter Thomas G.,
McKenna Sharon L.
Publication year - 2003
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.2003.04538.x
Subject(s) - phosphoinositide 3 kinase , cytosol , pi3k/akt/mtor pathway , chemistry , breakpoint cluster region , kinase , microbiology and biotechnology , cancer research , signal transduction , biology , biochemistry , enzyme , receptor
Summary. 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 ≈ 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, p21 WAF‐1 . Despite this, cells continue to cycle and are drug resistant. As p21 WAF‐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 p21 WAF‐1 are phosphinositide‐3‐kinase (PI3K) independent. Cytosolic p21 WAF‐1 has been reported to have a prosurvival role in other transformed cells. In Bcr‐Abl‐expressing cells, p21 WAF‐1 rapidly diminishes as the cells are sensitized to apoptosis, using the inhibitor STI571. It is possible therefore that p21 WAF‐1 could also have a positive, prosurvival role in these cells. This study suggests that, by retaining p21 WAF‐1 in a cytosolic location, Bcr‐Abl can evade the cell cycle arrest normally induced by nuclear p21 WAF‐1 and therefore also enable the cells to negate an important feature of a tumour suppressor response.