Transcription and signalling pathways involved in BCR-ABL-mediated misregulation of 24p3 and 24p3R
Programs in Gene Function and Expression; Program in Molecular Medicine
Medical Subject Headings
Animals; Core Binding Factor Alpha 2 Subunit; Down-Regulation; Female; Fusion Proteins, bcr-abl; Humans; Lipocalins; Male; Mice; Mice, Inbred Strains; Mice, SCID; Piperazines; Promoter Regions, Genetic; Proto-Oncogene Proteins p21(ras); Pyrimidines; Receptors, Cell Surface; *Signal Transduction; *Transcription, Genetic
Genetics and Genomics
Lipocalin 24p3 is a secreted protein that can induce apoptosis in cells containing the 24p3 cell surface receptor, 24p3R. The oncoprotein BCR-ABL activates 24p3 and represses 24p3R expression. Thus, BCR-ABL(+) cells synthesise and secrete 24p3, which induces apoptosis in normal 24p3R-containing cells but not in BCR-ABL(+) cells. The cell signalling and transcription factor pathways by which BCR-ABL misregulates expression of 24p3 and 24p3R remain to be elucidated. Here we show that BCR-ABL upregulates 24p3 expression through activation of the JAK/STAT pathway, which culminates in binding of Stat5 to the 24p3 promoter. We find that 24p3R expression is regulated by Runx transcription factors, and that BCR-ABL induces a switch in binding from Runx3, an activator of 24p3R expression, to Runx1, a repressor of 24p3R expression, through a Ras signalling pathway. Finally, we show that repression of 24p3R by BCR-ABL is a critical feature of the mechanism by which imatinib kills BCR-ABL(+) cells. Our results reveal diverse signalling/transcription pathways that regulate 24p3 and 24p3R expression in response to BCR-ABL and are directly relevant to the treatment of BCR-ABL(+) disease.
Rights and Permissions
Citation: EMBO J. 2009 Apr 8;28(7):866-76. Epub 2009 Feb 19. Link to article on publisher's site
Sheng, Zhi; Wang, Shu-Zong; and Green, Michael R., "Transcription and signalling pathways involved in BCR-ABL-mediated misregulation of 24p3 and 24p3R" (2009). Program in Gene Function and Expression Publications and Presentations. 81.