Down-regulation of BRCA1 in BCR-ABL-expressing hematopoietic cells.
BCR-ABL fusion oncogene is the molecular hallmark of chronic myelogenous leukemia (CML), a condition characterized by a progression from a chronic to acute phase leukemia because of secondary genetic events, the nature of which remains largely unknown. Here, we report that the expression of the p210 BCR-ABL fusion protein leads to a down-regulation of BRCA1 protein, a gene product involved in the maintenance of genome integrity. BRCA1 protein is nearly undetectable in leukemia cells from patients with CML, both during the chronic phase and in blast crisis. Similarly, stable transfection-enforced expression of p210 protein in established hematopoietic cell lines leads to severe BRCA1 depletion. The lack of significant change in BRCA1 mRNA level in cells expressing p210 supports the hypothesis that the regulation of BRCA1 protein level occurs after transcription. It is abolished on exposure of the cells to STI571 and by mutation in the adenosine triphosphate (ATP) pocket of p210 and thus seems to require the tyrosine kinase activity of BCR-ABL. Cell lines expressing high levels of BCR-ABL display an increased rate of sister chromatid exchange and chromosome aberrations after ionizing radiation. These findings reveal a novel link between the oncoprotein BCR-ABL and the tumor-suppressor protein BRCA1.
Deutsch
Eric
E
Department of Clinical Biology, Institut Gustave Roussy, Villejuif, France.
Jarrousse
Sylvie
S
Buet
Dorothee
D
Dugray
Aymeric
A
Bonnet
Marie-Laure
ML
Vozenin-Brotons
Marie-Catherine
MC
Guilhot
Francois
F
Turhan
Ali G
AG
Feunteun
Jean
J
Bourhis
Jean
J
D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism*; D001773:Blood Cells / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D004260:DNA Repair; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology; D051379:Mice; D012854:Sister Chromatid Exchange; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D019313:BRCA1 Protein; D016044:Fusion Proteins, bcr-abl