Abstract
The growth and survival of tumor cells in an unfavorable hypoxic environment depend upon their adaptability. Here, we show that both normal and tumor cells expressing the protein kinase Akt2 are more resistant to hypoxia than cells expressing Akt1 or Akt3. This is due to the differential regulation of microRNA (miR) 21, which is upregulated by hypoxia only in Akt2-expressing cells. By upregulating miR-21 upon oxygen deprivation, Akt2 downregulates PTEN and activates all three Akt isoforms. miR-21 also targets PDCD4 and Sprouty 1 (Spry1), and the combined downregulation of these proteins with PTEN is sufficient to confer resistance to hypoxia. Furthermore, the miR-21 induction by Akt2 during hypoxia depends upon the binding of NF-κB, cAMP responsive element-binding protein (CREB), and CBP/p300 to the miR-21 promoter, in addition to the regional acetylation of histone H3K9, all of which are under the control of Akt2. Analysis of the Akt2/miR-21 pathway in hypoxic MMTV-PyMT-induced mouse mammary adenocarcinomas and human ovarian carcinomas confirmed the activity of the pathway in vivo. Taken together, this study identifies a novel Akt2-dependent pathway that is activated by hypoxia and promotes tumor resistance via induction of miR-21.
©2011 AACR.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adenocarcinoma / enzymology
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism*
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Animals
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Apoptosis Regulatory Proteins / antagonists & inhibitors
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Apoptosis Regulatory Proteins / biosynthesis
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Cell Hypoxia / physiology
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Enzyme Activation
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Humans
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Isoenzymes
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Mammary Neoplasms, Experimental / enzymology
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism*
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / biosynthesis
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Mice
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MicroRNAs / biosynthesis*
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MicroRNAs / genetics
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Ovarian Neoplasms / enzymology
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism*
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Oxygen / metabolism
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PTEN Phosphohydrolase / biosynthesis
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PTEN Phosphohydrolase / genetics
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / biosynthesis
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Proto-Oncogene Proteins c-akt / biosynthesis
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA-Binding Proteins / antagonists & inhibitors
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RNA-Binding Proteins / biosynthesis
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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Isoenzymes
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MIRN21 microRNA, human
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MIRN21 microRNA, mouse
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Membrane Proteins
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MicroRNAs
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PDCD4 protein, human
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Pdcd4 protein, mouse
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Phosphoproteins
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RNA-Binding Proteins
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SPRY1 protein, human
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Spry1 protein, mouse
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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PTEN Phosphohydrolase
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Oxygen