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Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells.

Abstract The gradual emerging of resistance to imatinib urgently calls for the development of new therapy for chronic myeloid leukemia (CML). The fusion protein Bcr-Abl, which promotes the malignant transformation of CML cells, is mainly located in the cytoplasm, while the c-Abl protein which is expressed in the nucleus can induce apoptosis. Based on the hetero-dimerization of FKBP (the 12-kDa FK506- and rapamycin-binding protein) and FRB (the FKBP-rapamycin binding domain of the protein kinase, mTOR) mediated by AP21967, we constructed a nuclear transport system to induce cytoplasmic Bcr-Abl into nuclear. In this study, we reported the construction of the nuclear transport system, and we demonstrated that FN3R (three nuclear localization signals were fused to FRBT2098L with a FLAG tag), HF2S (two FKBP domains were in tandem and fused to the SH2 domain of Grb2 with an HA tag) and Bcr-Abl form a complexus upon AP21967. Bcr-Abl was imported into the nucleus successfully by the nuclear transport system. The nuclear transport system inhibited CML cell proliferation through mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (STAT5) pathways mainly by HF2S. It was proven that nuclear located Bcr-Abl induced CML cell (including imatinib-resistant K562G01 cells) apoptosis by activation of p73 and its downstream molecules. In summary, our study provides a new targeted therapy for the CML patients even with Tyrosine Kinase Inhibitor (TKI)-resistance.
PMID
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Authors

Mayor MeshTerms
Keywords

Bcr-Abl

apoptosis

nuclear

proliferation

transport

Journal Title international journal of molecular sciences
Publication Year Start




PMID- 28257089
OWN - NLM
STAT- MEDLINE
DA  - 20170303
DCOM- 20170317
LR  - 20170317
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 18
IP  - 3
DP  - 2017 Mar 02
TI  - Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and 
      Promotes Apoptosis in Chronic Myeloid Leukemia Cells.
LID - E537 [pii]
LID - 10.3390/ijms18030537 [doi]
AB  - The gradual emerging of resistance to imatinib urgently calls for the development
      of new therapy for chronic myeloid leukemia (CML). The fusion protein Bcr-Abl,
      which promotes the malignant transformation of CML cells, is mainly located in
      the cytoplasm, while the c-Abl protein which is expressed in the nucleus can
      induce apoptosis. Based on the hetero-dimerization of FKBP (the 12-kDa FK506- and
      rapamycin-binding protein) and FRB (the FKBP-rapamycin binding domain of the
      protein kinase, mTOR) mediated by AP21967, we constructed a nuclear transport
      system to induce cytoplasmic Bcr-Abl into nuclear. In this study, we reported the
      construction of the nuclear transport system, and we demonstrated that FN3R
      (three nuclear localization signals were fused to FRBT2098L with a FLAG tag),
      HF2S (two FKBP domains were in tandem and fused to the SH2 domain of Grb2 with an
      HA tag) and Bcr-Abl form a complexus upon AP21967. Bcr-Abl was imported into the 
      nucleus successfully by the nuclear transport system. The nuclear transport
      system inhibited CML cell proliferation through mitogen-activated protein kinase 
      (MAPK) and signal transducer and activator of transcription 5 (STAT5) pathways
      mainly by HF2S. It was proven that nuclear located Bcr-Abl induced CML cell
      (including imatinib-resistant K562G01 cells) apoptosis by activation of p73 and
      its downstream molecules. In summary, our study provides a new targeted therapy
      for the CML patients even with Tyrosine Kinase Inhibitor (TKI)-resistance.
FAU - Li, Qianyin
AU  - Li Q
AD  - Department of Clinical Hematology, Key Laboratory of Laboratory Medical
      Diagnostics Designated by the Ministry of Education, Chongqing Medical
      University, Chongqing 400016, China. lqianyincqmu@163.com.
FAU - Huang, Zhenglan
AU  - Huang Z
AD  - Department of Clinical Hematology, Key Laboratory of Laboratory Medical
      Diagnostics Designated by the Ministry of Education, Chongqing Medical
      University, Chongqing 400016, China. zhenglan_2@163.com.
FAU - Gao, Miao
AU  - Gao M
AD  - Department of Clinical Hematology, Key Laboratory of Laboratory Medical
      Diagnostics Designated by the Ministry of Education, Chongqing Medical
      University, Chongqing 400016, China. gaomiao_1@163.com.
FAU - Cao, Weixi
AU  - Cao W
AD  - Department of Clinical Hematology, Key Laboratory of Laboratory Medical
      Diagnostics Designated by the Ministry of Education, Chongqing Medical
      University, Chongqing 400016, China. weixicqmu@163.com.
FAU - Xiao, Qin
AU  - Xiao Q
AD  - Department of Hematology, The First Affiliated Hospital of Chongqing Medical
      University, Chongqing 400016, China. Xiaoqincqmufyy@163.com.
FAU - Luo, Hongwei
AU  - Luo H
AD  - Department of Clinical Hematology, Key Laboratory of Laboratory Medical
      Diagnostics Designated by the Ministry of Education, Chongqing Medical
      University, Chongqing 400016, China. luohongweicqmu@163.com.
FAU - Feng, Wenli
AU  - Feng W
AD  - Department of Clinical Hematology, Key Laboratory of Laboratory Medical
      Diagnostics Designated by the Ministry of Education, Chongqing Medical
      University, Chongqing 400016, China. fengwlcqmu@sina.com.
LA  - eng
PT  - Journal Article
DEP - 20170302
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (AP 21967)
RN  - 0 (Nuclear Localization Signals)
RN  - 0 (STAT5 Transcription Factor)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.10.2 (Fusion Proteins, bcr-abl)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Apoptosis
MH  - Cell Line, Tumor
MH  - Cell Nucleus/*metabolism
MH  - Cell Proliferation/drug effects
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Fusion Proteins, bcr-abl/chemistry/*metabolism
MH  - Humans
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/*metabolism
MH  - MAP Kinase Signaling System/drug effects
MH  - Nuclear Localization Signals/*pharmacology
MH  - Protein Transport/drug effects
MH  - STAT5 Transcription Factor/metabolism
MH  - Sirolimus/analogs & derivatives/pharmacology
MH  - Tyrosine/*antagonists & inhibitors
OTO - NOTNLM
OT  - Bcr-Abl
OT  - apoptosis
OT  - nuclear
OT  - proliferation
OT  - transport
EDAT- 2017/03/04 06:00
MHDA- 2017/03/18 06:00
CRDT- 2017/03/04 06:00
PHST- 2017/01/02 [received]
PHST- 2017/02/09 [revised]
PHST- 2017/02/23 [accepted]
AID - ijms18030537 [pii]
AID - 10.3390/ijms18030537 [doi]
PST - epublish
SO  - Int J Mol Sci. 2017 Mar 2;18(3). pii: E537. doi: 10.3390/ijms18030537.

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