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PMID:19057511

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Citation

Yu, J, Zhang, SS, Saito, K, Williams, S, Arimura, Y, Ma, Y, Ke, Y, Baron, V, Mercola, D, Feng, GS, Adamson, E and Mustelin, T (2009) PTEN regulation by Akt-EGR1-ARF-PTEN axis. EMBO J. 28:21-33

Abstract

The PTEN tumour suppressor gene is induced by the early growth response 1 (EGR1) transcription factor, which also transactivates p53, p73, and p300/CBP as well as other proapoptotic and anti-cancer genes. Here, we describe a novel Akt-EGR1-alternate reading frame (ARF)-PTEN axis, in which PTEN activation in vivo requires p14ARF-mediated sumoylation of EGR1. This modification is dependent on the phosphorylation of EGR1 at S350 and T309 by Akt, which promotes interaction of EGR1 with ARF at K272 in its repressor domain by the ARF/Ubc9/SUMO system. EGR1 sumoylation is decreased by ARF reduction, and no EGR1 sumoylation is detected in ARF(-/-) mice, which also exhibit reduced amounts of PTEN. Our model predicts that perturbation of any of the clinically important tumour suppressors, PTEN, EGR1, and ARF, will cause some degree of dysfunction of the others. These results also explain the known negative feedback regulation by PTEN on its own synthesis through PI3 kinase inhibition.

Links

PubMed PMC2633077 Online version:10.1038/emboj.2008.238

Keywords

Animals; Cell Line; Cyclin-Dependent Kinase Inhibitor p16/metabolism; Early Growth Response Protein 1/metabolism; Gene Expression Regulation; Humans; Mice; Mice, Knockout; Models, Biological; Oncogene Protein v-akt/metabolism; PTEN Phosphohydrolase/biosynthesis; Phosphorylation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:EGR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8N726

F

Seeded From UniProt

complete

HUMAN:EGR1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:EGR1

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:EGR1

involved_in

GO:0033233: regulation of protein sumoylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EGR1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ARF

involved_in

GO:0051091: positive regulation of DNA-binding transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ARF

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ARF

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P18146

F

Seeded From UniProt

complete

HUMAN:ARF

enables

GO:0061629: RNA polymerase II-specific DNA-binding transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P18146

F

Seeded From UniProt

complete

HUMAN:AKT1

involved_in

GO:0051091: positive regulation of DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT1

involved_in

GO:0001934: positive regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PTEN

involved_in

GO:0008285: negative regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:EGR1

involved_in

GO:0071480: cellular response to gamma radiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ARF

involved_in

GO:0033235: positive regulation of protein sumoylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ARF

enables

GO:0008134: transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P18146

F

Seeded From UniProt

complete


See also

References

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