Attenuation of DNA damage checkpoint by PBK, a novel mitotic kinase, involves protein-protein interaction with tumor suppressor p53

Asit K. Nandi, Tamara Ford, Daniel Fleksher, Brian J Neuman, Aaron P. Rapoport

Research output: Contribution to journalArticle

Abstract

Pathways adopted by developing cancer cells for evasion of cellular surveillance mechanism deserve attention for therapeutic exploitation as well as for better prognosis. A novel mitotic kinase, PDZ-binding kinase or PBK, which is upregulated in a variety of neoplasms including hematological malignancies, has been the focus of our attention with a goal to understand its role in malignant conversion and to examine as a possible new therapeutic target in disparate types of cancer. Earlier, we reported that PBK expression was downregulated during macrophage differentiation of HL60 promyelocytic leukemia cells, during doxorubicin-induced growth arrest in G2/M phase and that PBK was regulated by cell cycle-specific transcription factors E2F and CREB/ATF. Here, we demonstrate that HT1080 fibrosarcoma cells become adapted to doxorubicin-induced DNA damage checkpoint upon ectopic expression of a phosphomimetic mutant of PBK as indicated by the accumulation of polyploid cells. Aberrant entry into the mitotic phase by these cells is suggested by the appearance of a mitotic phase-specific marker, MPM-2. We propose that the effect is due to downregulation of p53 caused by direct physical interaction with PBK as detected by both a biochemical means as well as by yeast two-hybrid analysis. Together, our studies provide a plausible explanation for the role of PBK augmenting tumor cell growth following transient appearance in different types of progenitor cells in vivo as reported.

Original languageEnglish (US)
Pages (from-to)181-188
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume358
Issue number1
DOIs
StatePublished - Jun 22 2007
Externally publishedYes

Fingerprint

Protein Kinases
DNA Damage
Tumors
Phosphotransferases
Cells
Doxorubicin
DNA
E2F Transcription Factors
Neoplasms
Proteins
Macrophages
Cell growth
Down-Regulation
Yeast
Polyploidy
Fibrosarcoma
G2 Phase
Hematologic Neoplasms
Growth
Cell Division

Keywords

  • DNA damage checkpoint
  • Mitotic kinase
  • PDZ-binding kinase
  • Protein-protein interaction
  • Tumor suppressor p53

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Attenuation of DNA damage checkpoint by PBK, a novel mitotic kinase, involves protein-protein interaction with tumor suppressor p53. / Nandi, Asit K.; Ford, Tamara; Fleksher, Daniel; Neuman, Brian J; Rapoport, Aaron P.

In: Biochemical and Biophysical Research Communications, Vol. 358, No. 1, 22.06.2007, p. 181-188.

Research output: Contribution to journalArticle

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