BCR/ABL regulates expression of the cyclin-dependent kinase inhibitor p27Kip1 through the phosphatidylinositol 3-Kinase/AKT pathway.

TitleBCR/ABL regulates expression of the cyclin-dependent kinase inhibitor p27Kip1 through the phosphatidylinositol 3-Kinase/AKT pathway.
Publication TypeJournal Article
Year of Publication2000
AuthorsGesbert F, Sellers WR, Signoretti S, Loda M, Griffin JD
JournalJ Biol Chem
Date Published2000 Dec 15
KeywordsAnimals, Anti-Bacterial Agents, Benzamides, Cell Cycle, Cell Cycle Proteins, Cell Line, Cell Separation, Chromones, Cyclin-Dependent Kinase Inhibitor p27, Cycloheximide, Dose-Response Relationship, Drug, Down-Regulation, Doxycycline, Enzyme Activation, Enzyme Inhibitors, Fusion Proteins, bcr-abl, Genes, abl, Imatinib Mesylate, Interleukin-3, Mice, Microtubule-Associated Proteins, Morpholines, Phosphatidylinositol 3-Kinases, Piperazines, Promoter Regions, Genetic, Protein Synthesis Inhibitors, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Pyrimidines, Reverse Transcriptase Polymerase Chain Reaction, RNA, S Phase, Signal Transduction, Sirolimus, Time Factors, Transfection, Tumor Suppressor Proteins

Deregulation of cell cycle checkpoints is an almost universal abnormality in human cancers and is most often due to loss-of-function mutations of tumor suppressor genes such as Rb, p53, or p16(INK4a). In this study, we demonstrate that BCR/ABL inhibits the expression of a key cell cycle inhibitor, p27(Kip1), by signaling through a pathway involving phosphatidylinositol 3-kinase (PI3K). p27(Kip1) is a widely expressed inhibitor of cdk2, an essential cell cycle kinase regulating entry into S phase. We demonstrate that the decrease of p27(Kip1) is directly due to BCR/ABL in hematopoietic cells by two different approaches. First, induction of BCR/ABL by a tetracycline-regulated promoter is associated with a reversible down-regulation of p27(Kip1). Second, inhibition of BCR/ABL kinase activity with the Abl tyrosine kinase inhibitor STI571 rapidly increases p27(Kip1) levels. The PI3K inhibitor LY-294002 blocks the ability of BCR/ABL to induce p27(Kip1) down-regulation and inhibits BCR/ABL-induced entry into S phase. The serine/threonine kinase AKT/protein kinase B is a known downstream target of PI3K. Transient expression of an activated mutant of AKT was found to decrease expression of p27(Kip1), even when PI3K was inhibited by LY-294002. The mechanism of p27(Kip1) regulation is primarily related to protein stability, since inhibition of proteasome activity increased p27(Kip1) levels in BCR/ABL-transformed cells, whereas very little change in p27 transcription was found. Overall, these data are consistent with a model in which BCR/ABL suppresses p27(Kip1) protein levels through PI3K/AKT, leading to accelerated entry into S phase. This activity is likely to explain in part previous studies showing that activation of PI3K was required for optimum transformation of hematopoietic cells by BCR/ABL in vitro and in vivo.

Alternate JournalJ Biol Chem
PubMed ID11010972
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Massimo Loda, M.D.

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