Transcription and signalling pathways involved in BCR-ABL-mediated misregulation of 24p3 and 24p3R.
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Sheng Z, Wang SZ, Green MR
Transcription and signalling pathways involved in BCR-ABL-mediated misregulation of 24p3 and 24p3R.
EMBO J. 2009 Apr 8;28(7):866-76. doi: 10.1038/emboj.2009.35. Epub 2009 Feb 19.
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- 19229297 [ View in PubMed]
- 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.