Protein kinase CKIIalpha interacts with the Bcr moiety of Bcr/Abl and mediates proliferation of Bcr/Abl-expressing cells.
The Bcr protein was originally identified because of its fusion to Abl as a consequence of the Philadelphia chromosome translocation found in chronic myelogenous and acute lymphoblastic leukemias. The Bcr moiety is essential for the transforming activity of the Bcr/Abl oncogene. In search of physiologically relevant Bcr and Bcr/Abl-interacting proteins, we performed an interaction screen in yeast using the entire Bcr protein as bait. We here report that the alpha catalytic subunit of protein kinase CKII strongly and specifically forms a complex with Bcr in yeast in mouse lysates. The region in Bcr responsible for CKIIalpha binding was localized to residues 242-413. CKIIalpha was previously shown to be involved in leukemogenesis and tumorigenesis using different experimental approaches including mouse models. Inhibition of Bcr/Abl P190 in lymphoma cells from Bcr/Abl transgenic mice using imatinib reduced CKIIalpha activity. A highly selective inhibitor of CKIIalpha, 4,5,6,7-tetrabromo-2-benzotriazole, inhibited the growth of murine lymphoid cells with induced P210 Bcr/Abl expression and of P190 lymphoma cells. Our results demonstrate that CKIIalpha plays an important role in the proliferation of Bcr/Abl expressing cells, and suggests that inhibitors of CKIIalpha may have therapeutic potential in the treatment of Bcr/Abl-positive leukemia patients.
Mishra
Suparna
S
Section of Molecular Carcinogenesis, Division of Hematology/Oncology, Ms#54, Childrens Hospital of Los Angeles Research Institute 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.
Reichert
Anja
A
Cunnick
Jess
J
Senadheera
Dinithi
D
Hemmeryckx
Bianca
B
Heisterkamp
Nora
N
Groffen
John
J
D000818:Animals; D016466:CHO Cells; D047390:Casein Kinase II; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D020798:Two-Hybrid System Techniques
D004791:Enzyme Inhibitors; D016044:Fusion Proteins, bcr-abl; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases