Protein expression of PDZ-binding kinase is up-regulated in hematologic malignancies and strongly down-regulated during terminal differentiation of HL-60 leukemic cells

Asit Nandi, Michael Tidwell, Judith Karp, Aaron P. Rapoport

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)240-245
Number of pages6
JournalBlood Cells, Molecules, and Diseases
Volume32
Issue number1
DOIs
Publication statusPublished - Jan 2004
Externally publishedYes

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Keywords

  • Acute leukemia
  • c-Myc
  • Mitotic kinases
  • p38 MAP kinase
  • PBK
  • PBK/TOPK
  • PDZ-binding kinase
  • TOPK

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Hematology

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