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

J Biol Chem. 2000 Dec 15;275(50):39223-30. doi: 10.1074/jbc.M007291200.

Abstract

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.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Benzamides
  • Cell Cycle
  • Cell Cycle Proteins*
  • Cell Line
  • Cell Separation
  • Chromones / pharmacology
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cycloheximide / pharmacology
  • Dose-Response Relationship, Drug
  • Down-Regulation*
  • Doxycycline / pharmacology
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Fusion Proteins, bcr-abl / metabolism*
  • Genes, abl / genetics
  • Imatinib Mesylate
  • Interleukin-3 / pharmacology
  • Mice
  • Microtubule-Associated Proteins / metabolism*
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Piperazines / pharmacology
  • Promoter Regions, Genetic
  • Protein Synthesis Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Pyrimidines / pharmacology
  • RNA / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • S Phase / drug effects
  • Signal Transduction
  • Sirolimus / pharmacology
  • Time Factors
  • Transfection
  • Tumor Suppressor Proteins*

Substances

  • Anti-Bacterial Agents
  • Benzamides
  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • Chromones
  • Enzyme Inhibitors
  • Interleukin-3
  • Microtubule-Associated Proteins
  • Morpholines
  • Piperazines
  • Protein Synthesis Inhibitors
  • Proto-Oncogene Proteins
  • Pyrimidines
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • RNA
  • Imatinib Mesylate
  • Cycloheximide
  • Phosphatidylinositol 3-Kinases
  • Fusion Proteins, bcr-abl
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Doxycycline
  • Sirolimus