Bcr-Abl signaling through the PI-3/S6 kinase pathway inhibits nuclear translocation of the transcription factor Bach2, which represses the antiapoptotic factor heme oxygenase-1.
The malignant phenotype of chronic myeloid leukemia (CML) is due to the abnormal tyrosine kinase activity of the Bcr-Abl oncoprotein. We have previously reported that expression of the Bach2 transcription factor, which induces apoptosis in response to oxidative stress, is greatly reduced in CML cells. Because these cells are resistant to apoptosis, we tested whether Bach2 could also be regulated through posttranslational mechanisms that promote inhibition of the apoptotic response to mutagenic stimuli in CML. We found that Bach2 is phosphorylated on S521 via the phosphatidylinositol-3/S6 kinase pathway, and substitution of this site to alanine leads to nuclear accumulation of the protein, indicating that this phosphorylation is important for its subcellular localization. Ectopic expression of the S521 mutant imparts greater impairment to CML cell growth than the wild-type factor. Furthermore, we showed that Bach2 transcriptionally represses heme oxygenase-1, an antiapoptotic factor up-regulated in CML. Because CML cells are known to produce high levels of intracellular reactive oxygen species, overexpression of heme oxygenase-1 resulting from inhibition of Bach2 activity may contribute to their genomic instability and leukemic phenotype.
Yoshida
Chikashi
C
Department of Haematology, Imperial College London, Hammersmith Hospital, UK.
Yoshida
Fumiko
F
Sears
Daniel E
DE
Hart
Stephen M
SM
Ikebe
Dai
D
Muto
Akihiko
A
Basu
Subham
S
Igarashi
Kazuhiko
K
Melo
Junia V
JV
D021581:Active Transport, Cell Nucleus; D017209:Apoptosis; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology; D012097:Repressor Proteins; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction
C491123:BACH2 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D012097:Repressor Proteins; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl; D019893:Ribosomal Protein S6 Kinases