Members of the polo subfamily of Ser/Thr protein kinases have been shown to play critical roles for mitotic progression in various eukaryotic organisms. We have previously demonstrated that the evolutionarily conserved polo-box domain (PBD) of polo kinases is essential in targeting the catalytic activity of the polo kinases to specific subcellular structures. In an effort to identify the polo-box-binding proteins, we carried out yeast two-hybrid screening using the PBD of the mammalian polo-like kinase Plk1 as a bait and isolated a novel kinetochore-associating protein that we termed PBIP1 (for Polo-Box-Interacting Protein 1). PBIP1 interacts with endogenous Plk1 in vivo under physiological conditions and appears to be a kinetochore-specific mitotic inhibitor that is phosphorylated and degraded by Plk1 in mitosis. Expression of the non-degradable PBIP1 lacking the Plk1-dependent phosphorylation sites induces a mitotic arrest, indicating that degradation of PBIP1 is required for proper mitotic progression. PBIP1 binds to myeloid leukemia factor 1 (MLF1), whose deregulation by fusing with nuclear phosmin (NPM) promotes the development of acute myeloid leukemia (AML) from myelodysplasia (MDS). Thus, down-regulation of PBIP1 by MLF1 could be an important step for the development of AML. In line with these observations, we identified multiple mutations in the PLK1 ORF of leukemia cell lines. These findings raise the possibility that deregulation of Plk1 leads to improper PBIP1 function and the genesis of leukemia, and provide new views on the role of polo kinase in the development of leukemia and other tumoregenesis.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010520-03
Application #
7291869
Study Section
(LM)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Qian, Wen-Jian; Park, Jung-Eun; Grant, Robert et al. (2015) Neighbor-directed histidine N (?)-alkylation: A route to imidazolium-containing phosphopeptide macrocycles. Biopolymers 104:663-73
Qian, Wen-Jian; Park, Jung-Eun; Lim, Dan et al. (2014) Mono-anionic phosphopeptides produced by unexpected histidine alkylation exhibit high Plk1 polo-box domain-binding affinities and enhanced antiproliferative effects in HeLa cells. Biopolymers 102:444-55
Kang, Young H; Park, Chi Hoon; Kim, Tae-Sung et al. (2011) Mammalian polo-like kinase 1-dependent regulation of the PBIP1-CENP-Q complex at kinetochores. J Biol Chem 286:19744-57
Park, Jung-Eun; Li, Luowei; Park, Joobae et al. (2009) Direct quantification of polo-like kinase 1 activity in cells and tissues using a highly sensitive and specific ELISA assay. Proc Natl Acad Sci U S A 106:1725-30
Park, Chong J; Song, Sukgil; Giddings Jr, Thomas H et al. (2004) Requirement for Bbp1p in the proper mitotic functions of Cdc5p in Saccharomyces cerevisiae. Mol Biol Cell 15:1711-23