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Deregulated expression of Cdc6 as BCR/ABL-dependent survival factor in chronic myeloid leukemia cells.

Abstract Chronic myeloid leukemia is characterized by the presence of the reciprocal translocation t(9;22) and the BCR/ABL oncogene. The BCR/ABL oncogene activates multiple signaling pathways and involves the dysregulation of oncogenes during the progression of chronic myeloid leukemia. The cell division cycle protein 6, an essential regulator of DNA replication, is elevated in some human cancer cells. However, the expression of cell division cycle protein 6 in chronic myeloid leukemia and the underlying regulatory mechanism remain to be elucidated. In this study, our data showed that cell division cycle protein 6 expression was significantly upregulated in primary chronic myeloid leukemia cells and the chronic myeloid leukemia cell line K562 cells, as compared to the normal bone marrow mononuclear cells. BCR/ABL kinase inhibitor STI571 or BCR/ABL small interfering RNA could significantly downregulate cell division cycle protein 6 messenger RNA expression in K562 cells. Moreover, phosphoinositide 3-kinase/AKT pathway inhibitor LY294002 and Janus kinase/signal transducer and activator of transcription pathway inhibitor AG490 could downregulate cell division cycle protein 6 expression in K562 cells, but not RAS/mitogen-activated protein kinase pathway inhibitor PD98059 had such effect. Cell division cycle protein 6 gene silencing by small interfering RNA effectively resulted in decrease of proliferation, increase of apoptosis, and arrest of cell cycle in K562 cells. These findings have demonstrated that cell division cycle protein 6 overexpression may contribute to the high proliferation and low apoptosis in chronic myeloid leukemia cells and can be regulated by BCR/ABL signal transduction through downstream phosphoinositide 3-kinase/Akt and Janus kinase/signal transducer and activator of transcription pathways, suggesting cell division cycle protein 6 as a potential therapeutic target in chronic myeloid leukemia.
PMID
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Authors

Mayor MeshTerms
Keywords

BCR/ABL

Cell division cycle protein 6

K562 cells

chronic myeloid leukemia

survival factor

Journal Title tumour biology : the journal of the international society for oncodevelopmental biology and medicine
Publication Year Start




PMID- 28639894
OWN - NLM
STAT- MEDLINE
DA  - 20170622
DCOM- 20170711
LR  - 20170713
IS  - 1423-0380 (Electronic)
IS  - 1010-4283 (Linking)
VI  - 39
IP  - 6
DP  - 2017 Jun
TI  - Deregulated expression of Cdc6 as BCR/ABL-dependent survival factor in chronic
      myeloid leukemia cells.
PG  - 1010428317713394
LID - 10.1177/1010428317713394 [doi]
AB  - Chronic myeloid leukemia is characterized by the presence of the reciprocal
      translocation t(9;22) and the BCR/ABL oncogene. The BCR/ABL oncogene activates
      multiple signaling pathways and involves the dysregulation of oncogenes during
      the progression of chronic myeloid leukemia. The cell division cycle protein 6,
      an essential regulator of DNA replication, is elevated in some human cancer
      cells. However, the expression of cell division cycle protein 6 in chronic
      myeloid leukemia and the underlying regulatory mechanism remain to be elucidated.
      In this study, our data showed that cell division cycle protein 6 expression was 
      significantly upregulated in primary chronic myeloid leukemia cells and the
      chronic myeloid leukemia cell line K562 cells, as compared to the normal bone
      marrow mononuclear cells. BCR/ABL kinase inhibitor STI571 or BCR/ABL small
      interfering RNA could significantly downregulate cell division cycle protein 6
      messenger RNA expression in K562 cells. Moreover, phosphoinositide 3-kinase/AKT
      pathway inhibitor LY294002 and Janus kinase/signal transducer and activator of
      transcription pathway inhibitor AG490 could downregulate cell division cycle
      protein 6 expression in K562 cells, but not RAS/mitogen-activated protein kinase 
      pathway inhibitor PD98059 had such effect. Cell division cycle protein 6 gene
      silencing by small interfering RNA effectively resulted in decrease of
      proliferation, increase of apoptosis, and arrest of cell cycle in K562 cells.
      These findings have demonstrated that cell division cycle protein 6
      overexpression may contribute to the high proliferation and low apoptosis in
      chronic myeloid leukemia cells and can be regulated by BCR/ABL signal
      transduction through downstream phosphoinositide 3-kinase/Akt and Janus
      kinase/signal transducer and activator of transcription pathways, suggesting cell
      division cycle protein 6 as a potential therapeutic target in chronic myeloid
      leukemia.
FAU - Zhang, Jia-Hua
AU  - Zhang JH
AD  - 1 Center for Stem Cell Research and Application, Union Hospital, Tongji Medical
      College, Huazhong University of Science & Technology, Wuhan, China.
FAU - He, Yan-Li
AU  - He YL
AD  - 1 Center for Stem Cell Research and Application, Union Hospital, Tongji Medical
      College, Huazhong University of Science & Technology, Wuhan, China.
FAU - Zhu, Rui
AU  - Zhu R
AD  - 2 Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji
      Medical College, Huazhong University of Science & Technology, Wuhan, China.
FAU - Du, Wen
AU  - Du W
AD  - 1 Center for Stem Cell Research and Application, Union Hospital, Tongji Medical
      College, Huazhong University of Science & Technology, Wuhan, China.
FAU - Xiao, Jun-Hua
AU  - Xiao JH
AD  - 3 Department of Pharmacology, Tongji Medical College, Huazhong University of
      Science & Technology, Wuhan, China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Tumour Biol
JT  - Tumour biology : the journal of the International Society for Oncodevelopmental
      Biology and Medicine
JID - 8409922
RN  - 0 (BCR-ABL1 fusion protein, human)
RN  - 0 (Benzamides)
RN  - 0 (CDC6 protein, human)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Piperazines)
RN  - 0 (Pyrimidines)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - EC 2.7.10.2 (Fusion Proteins, bcr-abl)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Benzamides/administration & dosage
MH  - Cell Cycle Proteins/*biosynthesis/genetics
MH  - Cell Division/*drug effects
MH  - Fusion Proteins, bcr-abl/*genetics
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Imatinib Mesylate/administration & dosage
MH  - K562 Cells
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/*genetics/pathology
MH  - Nuclear Proteins/*biosynthesis/genetics
MH  - Piperazines/administration & dosage
MH  - Pyrimidines/administration & dosage
MH  - Signal Transduction/drug effects
OTO - NOTNLM
OT  - BCR/ABL
OT  - Cell division cycle protein 6
OT  - K562 cells
OT  - chronic myeloid leukemia
OT  - survival factor
EDAT- 2017/06/24 06:00
MHDA- 2017/07/14 06:00
CRDT- 2017/06/23 06:00
AID - 10.1177/1010428317713394 [doi]
PST - ppublish
SO  - Tumour Biol. 2017 Jun;39(6):1010428317713394. doi: 10.1177/1010428317713394.