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Mirk/dyrk1B kinase is upregulated following inhibition of mTOR.
- Source :
-
Carcinogenesis [Carcinogenesis] 2014 Sep; Vol. 35 (9), pp. 1968-76. Date of Electronic Publication: 2014 Mar 03. - Publication Year :
- 2014
-
Abstract
- 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.<br /> (© The Author 2014. Published by Oxford University Press.)
- Subjects :
- Cell Line, Tumor
Chromones pharmacology
Cyclic AMP Response Element-Binding Protein metabolism
Drug Synergism
Enzyme Activation
Everolimus
Gene Expression
Gene Expression Regulation, Neoplastic drug effects
Humans
Morpholines pharmacology
Promoter Regions, Genetic
Protein Serine-Threonine Kinases antagonists & inhibitors
Protein Serine-Threonine Kinases genetics
Protein-Tyrosine Kinases antagonists & inhibitors
Protein-Tyrosine Kinases genetics
Proto-Oncogene Proteins c-akt metabolism
RNA, Messenger genetics
RNA, Messenger metabolism
Signal Transduction
Sirolimus analogs & derivatives
Sirolimus pharmacology
TOR Serine-Threonine Kinases antagonists & inhibitors
Dyrk Kinases
Protein Serine-Threonine Kinases metabolism
Protein-Tyrosine Kinases metabolism
TOR Serine-Threonine Kinases metabolism
Up-Regulation drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2180
- Volume :
- 35
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Carcinogenesis
- Publication Type :
- Academic Journal
- Accession number :
- 24590896
- Full Text :
- https://doi.org/10.1093/carcin/bgu058