Transcription and signalling pathways involved in BCR-ABL-mediated misregulation of 24p3 and 24p3R.
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.
Sheng
Zhi
Z
Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Wang
Shu-Zong
SZ
Green
Michael R
MR
D000818:Animals; D001549:Benzamides; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D054834:Lipocalins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
D001549:Benzamides; D050676:Core Binding Factor Alpha 2 Subunit; D054834:Lipocalins; D010879:Piperazines; D011743:Pyrimidines; D011956:Receptors, Cell Surface; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D016283:Proto-Oncogene Proteins p21(ras)