PMID- 24590896
OWN - NLM
STAT- MEDLINE
DCOM- 20141021
LR  - 20231213
IS  - 1460-2180 (Electronic)
IS  - 0143-3334 (Print)
IS  - 0143-3334 (Linking)
VI  - 35
IP  - 9
DP  - 2014 Sep
TI  - Mirk/dyrk1B kinase is upregulated following inhibition of mTOR.
PG  - 1968-76
LID - 10.1093/carcin/bgu058 [doi]
AB  - The PI3K/PTEN/Akt/mTOR/p70S6K pathway is one of the most frequently deregulated 
      signaling pathways in solid tumors and has a functional role in drug resistance. 
      However, targeting this pathway leads to compensatory activation of several 
      mediators of cell survival. Expression of the reactive oxygen species-controlling 
      kinase Mirk/dyrk1B was increased severalfold by the mammalian target of rapamycin 
      (mTOR) inhibitors RAD001, WYE354 and rapamycin, with less effect by the Akt 
      inhibitors AZD5363 and MK-2206. Upregulation of Mirk messenger RNA (mRNA) 
      expression was mediated by cyclic AMP response element binding protein (CREB) 
      binding to two sites in the Mirk promoter upstream of the transcription start 
      site and one site within exon 4. Depletion of CREB reduced Mirk expression, 
      whereas depletion of mTOR increased it. Moreover, hydroxytamoxifen activation of 
      an Akt-estrogen receptor construct blocked an increase in Mirk mRNA and protein. 
      Addition of a Mirk/dyrk1B kinase inhibitor increased the sensitivity of Panc1 
      pancreatic cancer cells and three different ovarian cancer cell lines to the mTOR 
      inhibitor RAD001. Targeting Mirk kinase could improve the utility of mTOR 
      inhibitors and so presents an attractive drug target.
CI  - (c) The Author 2014. Published by Oxford University Press.
FAU - Deng, Xiaobing
AU  - Deng X
AD  - Department of Pathology, SUNY Upstate Medical University, Syracuse, NY 13210, 
      USA.
FAU - Hu, Jing
AU  - Hu J
AD  - Department of Pathology, SUNY Upstate Medical University, Syracuse, NY 13210, 
      USA.
FAU - Ewton, Daina Z
AU  - Ewton DZ
AD  - Department of Pathology, SUNY Upstate Medical University, Syracuse, NY 13210, 
      USA.
FAU - Friedman, Eileen
AU  - Friedman E
AD  - Department of Pathology, SUNY Upstate Medical University, Syracuse, NY 13210, USA 
      friedmae@upstate.edu.
LA  - eng
GR  - CA13516402/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140303
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (CREB1 protein, human)
RN  - 0 (Chromones)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Morpholines)
RN  - 0 (RNA, Messenger)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Cell Line, Tumor
MH  - Chromones/pharmacology
MH  - Cyclic AMP Response Element-Binding Protein/metabolism
MH  - Drug Synergism
MH  - Enzyme Activation
MH  - Everolimus
MH  - Gene Expression
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Morpholines/pharmacology
MH  - Promoter Regions, Genetic
MH  - Protein Serine-Threonine Kinases/antagonists & inhibitors/genetics/*metabolism
MH  - Protein-Tyrosine Kinases/antagonists & inhibitors/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - RNA, Messenger/genetics/metabolism
MH  - Signal Transduction
MH  - Sirolimus/analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
MH  - Up-Regulation/*drug effects
MH  - Dyrk Kinases
PMC - PMC4146409
EDAT- 2014/03/05 06:00
MHDA- 2014/10/22 06:00
PMCR- 2014/03/03
CRDT- 2014/03/05 06:00
PHST- 2014/03/05 06:00 [entrez]
PHST- 2014/03/05 06:00 [pubmed]
PHST- 2014/10/22 06:00 [medline]
PHST- 2014/03/03 00:00 [pmc-release]
AID - bgu058 [pii]
AID - 10.1093/carcin/bgu058 [doi]
PST - ppublish
SO  - Carcinogenesis. 2014 Sep;35(9):1968-76. doi: 10.1093/carcin/bgu058. Epub 2014 Mar 
      3.