PMID- 23300087
OWN - NLM
STAT- MEDLINE
DCOM- 20130509
LR  - 20211203
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 288
IP  - 9
DP  - 2013 Mar 1
TI  - Reprogramming of the microRNA transcriptome mediates resistance to rapamycin.
PG  - 6034-44
LID - 10.1074/jbc.M112.416446 [doi]
AB  - The mammalian target of rapamycin (mTOR) is a central regulator of cell 
      proliferation that is often deregulated in cancer. Inhibitors of mTOR, including 
      rapamycin and its analogues, are being evaluated as antitumor agents. For their 
      promise to be fulfilled, it is of paramount importance to identify the mechanisms 
      of resistance and develop novel therapies to overcome it. Given the emerging role 
      of microRNAs (miRNAs) in tumorigenesis, we hypothesized that miRNAs could play 
      important roles in the response of tumors to mTOR inhibitors. Long-term rapamycin 
      treatment showed extensive reprogramming of miRNA expression, characterized by 
      up-regulation of miR-17-92 and related clusters and down-regulation of tumor 
      suppressor miRNAs. Inhibition of members of the miR-17-92 clusters or delivery of 
      tumor suppressor miRNAs restored sensitivity to rapamycin. This study identifies 
      miRNAs as new downstream components of the mTOR-signaling pathway, which may 
      determine the response of tumors to mTOR inhibitors. It also identifies potential 
      markers to assess the efficacy of treatment and provides novel therapeutic 
      targets to treat rapamycin-resistant tumors.
FAU - Totary-Jain, Hana
AU  - Totary-Jain H
AD  - Department of Physiology and Cellular Biophysics, the Clyde and Helen Wu Center 
      for Molecular Cardiology, Columbia University, New York, New York 10032, USA. 
      ht2167@columbia.edu
FAU - Sanoudou, Despina
AU  - Sanoudou D
FAU - Ben-Dov, Iddo Z
AU  - Ben-Dov IZ
FAU - Dautriche, Cula N
AU  - Dautriche CN
FAU - Guarnieri, Paolo
AU  - Guarnieri P
FAU - Marx, Steven O
AU  - Marx SO
FAU - Tuschl, Thomas
AU  - Tuschl T
FAU - Marks, Andrew R
AU  - Marks AR
LA  - eng
SI  - GEO/GSE19944
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - F32HL088815/HL/NHLBI NIH HHS/United States
GR  - F32 HL088815/HL/NHLBI NIH HHS/United States
GR  - K99 HL109133/HL/NHLBI NIH HHS/United States
GR  - K99HL109133/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130108
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (MIRN17-92 microRNA, mouse)
RN  - 0 (MicroRNAs)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (RNA, Neoplasm)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - Mice
MH  - MicroRNAs/*biosynthesis
MH  - Neoplasm Proteins/metabolism
MH  - RNA, Neoplasm/*biosynthesis
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Time Factors
MH  - Transcriptome/*drug effects
PMC - PMC3585042
EDAT- 2013/01/10 06:00
MHDA- 2013/05/10 06:00
PMCR- 2014/03/01
CRDT- 2013/01/10 06:00
PHST- 2013/01/10 06:00 [entrez]
PHST- 2013/01/10 06:00 [pubmed]
PHST- 2013/05/10 06:00 [medline]
PHST- 2014/03/01 00:00 [pmc-release]
AID - S0021-9258(20)43498-2 [pii]
AID - M112.416446 [pii]
AID - 10.1074/jbc.M112.416446 [doi]
PST - ppublish
SO  - J Biol Chem. 2013 Mar 1;288(9):6034-44. doi: 10.1074/jbc.M112.416446. Epub 2013 
      Jan 8.