Transcription and signalling pathways involved in BCR-ABL-mediated misregulation of 24p3 and 24p3R
Sheng, Zhi ; Wang, Shu-Zong ; Green, Michael R.
Citations
Student Authors
Faculty Advisor
Academic Program
UMass Chan Affiliations
Document Type
Publication Date
Keywords
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
Subject Area
Embargo Expiration Date
Link to Full Text
Abstract
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.
Source
EMBO J. 2009 Apr 8;28(7):866-76. Epub 2009 Feb 19. Link to article on publisher's site