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PMID:20208519

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Citation

Chen, D, Shan, J, Zhu, WG, Qin, J and Gu, W (2010) Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses. Nature 464:624-7

Abstract

The tumour suppressor ARF is specifically required for p53 activation under oncogenic stress. Recent studies showed that p53 activation mediated by ARF, but not that induced by DNA damage, acts as a major protection against tumorigenesis in vivo under certain biological settings, suggesting that the ARF-p53 axis has more fundamental functions in tumour suppression than originally thought. Because ARF is a very stable protein in most human cell lines, it has been widely assumed that ARF induction is mediated mainly at the transcriptional level and that activation of the ARF-p53 pathway by oncogenes is a much slower and largely irreversible process by comparison with p53 activation after DNA damage. Here we report that ARF is very unstable in normal human cells but that its degradation is inhibited in cancerous cells. Through biochemical purification, we identified a specific ubiquitin ligase for ARF and named it ULF. ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF. ULF knockdown stabilizes ARF in normal human cells, triggering ARF-dependent, p53-mediated growth arrest. Moreover, nucleophosmin (NPM) and c-Myc, both of which are commonly overexpressed in cancer cells, are capable of abrogating ULF-mediated ARF ubiquitylation through distinct mechanisms, and thereby promote ARF stabilization in cancer cells. These findings reveal the dynamic feature of the ARF-p53 pathway and suggest that transcription-independent mechanisms are critically involved in ARF regulation during responses to oncogenic stress.

Links

PubMed PMC3737736 Online version:10.1038/nature08820

Keywords

ADP-Ribosylation Factors/metabolism; Cell Line; Fibroblasts/metabolism; Gene Expression Regulation; Humans; Molecular Sequence Data; Nuclear Proteins/metabolism; Proto-Oncogene Proteins c-myc/metabolism; Stress, Physiological/physiology; Tumor Suppressor Protein p53/metabolism; U937 Cells; Ubiquitin-Protein Ligases/metabolism; Ubiquitination

Significance

Annotations

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

HUMAN:MYC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14669

F

Seeded From UniProt

complete

HUMAN:NPM

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14669

F

Seeded From UniProt

complete

HUMAN:TRIPC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8N726

F

Seeded From UniProt

complete

HUMAN:TRIPC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P01106

F

Seeded From UniProt

complete

HUMAN:TRIPC

located_in

GO:0005654: nucleoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TRIPC

involved_in

GO:0006511: ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TRIPC

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TRIPC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P06748-1

F

Seeded From UniProt

complete

HUMAN:ARF

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14669

F

Seeded From UniProt

complete

See also

References

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