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

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.

• Authors: Asit K Nandi, Tamara Ford, Daniel Fleksher, Brian Neuman, Aaron P Rapoport
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 358 Issue 1 Pg. 181-8 (Jun 22 2007) ISSN: 0006-291X [Print] United States
• PMID: 17482142 (Publication Type: Journal Article)

Chemical References

• Antibiotics, Antineoplastic
• Cell Cycle Proteins
• Tumor Suppressor Protein p53
• Doxorubicin
• Protein Serine-Threonine Kinases
• Mitogen-Activated Protein Kinase Kinases
• PDZ-binding kinase

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Cell Cycle
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• DNA Damage
• Down-Regulation
• Doxorubicin (pharmacology)
• Humans
• Mitogen-Activated Protein Kinase Kinases
• Mutation
• Protein Binding
• Protein Serine-Threonine Kinases (biosynthesis, genetics, physiology)
• Tumor Suppressor Protein p53 (metabolism)