Attenuation of DNA damage checkpoint by PBK, a novel mitotic kinase, involves protein-protein interaction with tumor suppressor p53.
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.
Nandi
Asit K
AK
Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA. anandi@som.umaryland.edu
Ford
Tamara
T
Fleksher
Daniel
D
Neuman
Brian
B
Rapoport
Aaron P
AP
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases; D009154:Mutation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D017346:Protein Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C409022:PDZ-binding kinase