PMID- 26503118
OWN - NLM
STAT- MEDLINE
DCOM- 20160808
LR  - 20171116
IS  - 1791-2431 (Electronic)
IS  - 1021-335X (Linking)
VI  - 34
IP  - 6
DP  - 2015 Dec
TI  - PBK/TOPK mediates promyelocyte proliferation via Nrf2-regulated cell cycle 
      progression and apoptosis.
PG  - 3288-96
AB  - Acute myeloid leukemia (AML) is a disorder involving hematopoietic stem cells, 
      characterized by blockage of hematopoietic cell differentiation and an increase 
      in clonal neoplastic proliferation. AML is associated with poor patient outcome. 
      PBK/TOPK is a protein kinase derived from PDZ-binding kinase 
      (PBK)/T-lymphokine-activated killer (T-LAK) cell-originated protein kinase 
      (TOPK). Previous studies have shown that PBK/TOPK is expressed in hematologic 
      tumors. In the present study, we aimed to investigate the role of PBK/TOPK in 
      promyelocyte proliferation and to clarify the molecular mechanism. PBK/TOPK 
      knockdown (KD) significantly decreased cell proliferation and viability in the 
      NB4 and HL-60 promyelocytes. PBK/TOPK KD resulted in G2/M cell cycle arrest that 
      attributed to a decrease in cdc2 and cyclin B expression. In addition, PBK/TOPK 
      KD caused apoptosis, as evidenced by activation of the mitochondrial apoptotic 
      pathway and an increase in TUNEL-positive cells. PBK/TOPK KD induced 
      mitochondrial dysfunction and ROS generation, and inhibition of mitochondrial 
      dysfunction and ROS production suppressed PBK/TOPK KD-induced cell cycle arrest 
      and apoptosis. Moreover, PBK/TOPK KD decreased Nrf2 expression and ARE-binding 
      activity. Overexpression of Nrf2 inhibited the PBK/TOPK KD-induced decrease in 
      cdc2 and cyclin B expression and cell cycle arrest, and blocked ROS production 
      and apoptosis. Based on literature and our results, it was demonstrated that Nrf2 
      may be a crucial regulator that mediates PBK/TOPK-exerted promotion of cell 
      proliferation. PBK/TOPK stabilizes Nrf2, strictly regulates the ROS level, 
      promotes cell cycle progression and inhibits apoptosis, contributing to the 
      proliferation of promyelocytes. Our results provide new insights into the 
      molecular mechanism of PBK/TOPK-mediated promyelocyte proliferation and shed 
      light on the pathogenesis of AML.
FAU - Liu, Yuhong
AU  - Liu Y
FAU - Liu, Hui
AU  - Liu H
FAU - Cao, Huiqin
AU  - Cao H
FAU - Song, Bin
AU  - Song B
FAU - Zhang, Wen
AU  - Zhang W
FAU - Zhang, Wanggang
AU  - Zhang W
LA  - eng
PT  - Journal Article
PL  - Greece
TA  - Oncol Rep
JT  - Oncology reports
JID - 9422756
RN  - 0 (Cyclin B)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 2.7.11.22 (CDC2 Protein Kinase)
RN  - EC 2.7.11.22 (CDK1 protein, human)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 2.7.12.2 (PDZ-binding kinase)
SB  - IM
MH  - Apoptosis/genetics
MH  - CDC2 Protein Kinase
MH  - Cell Cycle Checkpoints/genetics
MH  - Cell Differentiation/genetics
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*genetics
MH  - Cyclin B/biosynthesis
MH  - Cyclin-Dependent Kinases/biosynthesis
MH  - Gene Expression Regulation, Leukemic
MH  - Granulocyte Precursor Cells/metabolism/pathology
MH  - HL-60 Cells
MH  - Hematopoietic Stem Cells/metabolism/pathology
MH  - Humans
MH  - Leukemia, Myeloid, Acute/*genetics/pathology
MH  - Mitogen-Activated Protein Kinase Kinases/*biosynthesis/genetics
MH  - NF-E2-Related Factor 2/biosynthesis/*genetics
MH  - Reactive Oxygen Species/metabolism
EDAT- 2015/10/28 06:00
MHDA- 2016/08/09 06:00
CRDT- 2015/10/28 06:00
PHST- 2015/06/04 00:00 [received]
PHST- 2015/07/13 00:00 [accepted]
PHST- 2015/10/28 06:00 [entrez]
PHST- 2015/10/28 06:00 [pubmed]
PHST- 2016/08/09 06:00 [medline]
AID - 10.3892/or.2015.4308 [doi]
PST - ppublish
SO  - Oncol Rep. 2015 Dec;34(6):3288-96. doi: 10.3892/or.2015.4308.