Protein expression of PDZ-binding kinase is up-regulated in hematologic malignancies and strongly down-regulated during terminal differentiation of HL-60 leukemic cells.
PBK/TOPK is a recently identified 322 amino acid serine/threonine kinase that is phosphorylated during mitosis and may include p38 MAPK among its targets. Previous work has shown up-regulated expression of PBK/TOPK mRNA in a variety of tumor cell lines and fetal tissues, suggesting a role for this kinase in malignant cell proliferation. In this paper, PBK/TOPK protein expression was examined in a variety of primary hematologic neoplasms: PBK/TOPK was readily detected in 9 of 12 AML samples (75%), in 3 of 3 ALL samples, and in 1 sample each of a plasmacytoma and blastic type mantle cell lymphoma where it was strongly expressed. In contrast, PBK/TOPK was only weakly expressed in 2 samples of G-CSF-mobilized peripheral blood stem cells that were enriched in CD34+ progenitors by immunoselection. Furthermore, when HL-60 myeloid leukemic cells were differentiated with phorbol ester (TPA), PBK/TOPK protein expression was strongly down-regulated by 24 h. Under these same conditions, phosphorylated c-Myc was rapidly down-regulated (by 4 h), while the levels of cyclin D1 and phosphorylated p38 were constant. Notably, of 5 clinical samples that strongly expressed PBK/TOPK, 4 also strongly expressed phosphorylated c-Myc, while only 1 of 3 PBK/TOPK negative samples expressed phosphorylated c-Myc. These data show that PBK/TOPK protein is up-regulated in a variety of hematologic malignancies and may be involved in leukemic cell growth. Additional studies are warranted to determine if PBK/TOPK would be a valuable target for novel therapeutics. To this end, we also describe the derivation of clones of 293 (human embryonic kidney) cells, which carry an inducible kinase-defective mutant of PBK/TOPK. This model may be useful for studying the effects of down-regulated PBK/TOPK function.
Nandi
Asit
A
Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA.
Tidwell
Michael
M
Karp
Judith
J
Rapoport
Aaron P
AP
D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D015536:Down-Regulation; D018922:HL-60 Cells / Q000201:enzymology*; D019337:Hematologic Neoplasms / Q000201:enzymology*; D006412:Hematopoietic Stem Cells / Q000201:enzymology; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation
C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D017346:Protein Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C409022:PDZ-binding kinase; D013755:Tetradecanoylphorbol Acetate