Bcr: a negative regulator of the Bcr-Abl oncoprotein in leukemia

Abstract

The fusion of 5' parts of the BCR gene to the ABL gene at the second exon yields several forms of an oncogenic Bcr-Abl oncoprotein observed in several types of Philadelphia chromosome positive leukemia patients. The first exon of the BCR gene is a critical part of this fusion, as the coiled-coil domain at the amino terminal domain of the Bcr protein causes oligomerization of the Bcr-Abl oncoprotein forming tetramers, thereby activating the tyrosine kinase activity of the normally silent c-Abl protein. Another consequence of this Bcr-Abl fusion is the extensive autophosphorylation of the cis Bcr protein sequences on tyrosine residues. This review will summarize the effects of Bcr-Abl autophosphorylation on tyrosines as they relate to the oncogenic activity of Bcr-Abl, and as a means to inactivate the serine/threonine kinase activity of the Bcr protein. The review also discusses our findings that show that phosphoserine Bcr by means of a unique structure, binds to the Abl SH2 domain of the Bcr-Abl oncoprotein, and as a result this SH2 binding inhibits the oncogenic effects of the oncoprotein. Our results indicate that one effect of this binding is inhibition of the Bcr-Abl tyrosine kinase. Serine 354 of Bcr plays a major role in this inhibition. In the case of Bcr(64-413), serine 354 is required for the formation of the unique Bcr structure that binds to the Abl SH2 domain.

MUC1 Oncoprotein Regulates Bcr-Abl Stability and Pathogenesis in Chronic Myelogenous Leukemia Cells

“…However, MUC1-C Tyr 60 is not required for binding to Bcr-Abl (data not shown), consistent with the interaction between MUC1-CD and Bcr. Bcr is a negative regulator of Bcr-Abl by mechanisms that are unclear (41,42). In this context, Bcr could compete with Bcr-Abl for binding to MUC1-C in CML cells.…”

Kinase domain mutants of Bcr enhance Bcr-Abl oncogenic effects

“…As a consequence, these clones have reduced ability to induce extramedullary leukemia (Lin et al, 2001). On the basis of these results, we have proposed that the Bcr protein plays two roles in CML (Arlinghaus, 2002). In the tyrosine-phosphorylated form, Bcr would be neutralized as an inhibitor of Bcr-Abl effects and would serve as an important facilitator of Bcr-Abl-induced leukemia, possibly in the form of a heterotetramer structure with Bcr-Abl (McWhirter et al, 1993).…”

The perichromosomal layer

“…Disruption of the breakpoint cluster region (BCR) gene and its juxtaposition next to the AbeLson (ABL) gene, comprising the Philadelphia translocation, have been implicated as critical molecular defects leading to certain leukemias (Arlinghaus 2002). The transforming function of this translocation is due to the activation of ABL tyrosine kinase by BCR sequences.…”