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PMID:15526030

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Citation

Rui, Y, Xu, Z, Lin, S, Li, Q, Rui, H, Luo, W, Zhou, HM, Cheung, PY, Wu, Z, Ye, Z, Li, P, Han, J and Lin, SC (2004) Axin stimulates p53 functions by activation of HIPK2 kinase through multimeric complex formation. EMBO J. 23:4583-94

Abstract

Axin and p53 are tumor suppressors, controlling cell growth, apoptosis, and development. We show that Axin interacts with homeodomain-interacting protein kinase-2 (HIPK2), which is linked to UV-induced p53-dependent apoptosis by interacting with, and phosphorylating Ser 46 of, p53. In addition to association with p53 via HIPK2, Axin contains a separate domain that directly interacts with p53 at their physiological concentrations. Axin stimulates p53-dependent reporter transcription in 293 cells, but not in 293T, H1299, or SaOS-2 cells that are defective in p53 signaling. Axin, but not AxindeltaHIPK2, activates HIPK2-mediated p53 phosphorylation at Ser 46, facilitating p53-dependent transcriptional activity and apoptosis. Specific knockdown of Axin by siRNA reduced UV-induced Ser-46 phosphorylation and apoptosis. Kinase-dead HIPK2 reduced Axin-induced p53-dependent transcriptional activity, indicating that Axin stimulates p53 function through HIPK2 kinase activity. Interestingly, HIPK2deltaAxin that lacks its Axin-binding region acts as a dominant-positive form in p53 activation, suggesting that the Axin-binding region of HIPK2 is a putative autoinhibitory domain. These results show that Axin acts as a tumor suppressor by facilitating p53 function through integration of multiple factors.

Links

PubMed PMC533058 Online version:10.1038/sj.emboj.7600475

Keywords

Apoptosis/physiology; Apoptosis/radiation effects; Axin Protein; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Line, Tumor; Enzyme Activation; Genes, Reporter; Humans; Mutation; Phosphorylation; Protein Binding; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; RNA, Small Interfering/pharmacology; Repressor Proteins/genetics; Repressor Proteins/metabolism; Repressor Proteins/physiology; Serine/metabolism; Transcription, Genetic; Tumor Suppressor Protein p53/metabolism; Tumor Suppressor Protein p53/physiology; Ultraviolet Rays

Significance

Annotations

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

MOUSE:AXIN1

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9QZR5

F

Seeded From UniProt

complete

MOUSE:AXIN1

enables

GO:0002039: p53 binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P02340

F

Seeded From UniProt

complete

MOUSE:P53

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:O35625
PR:Q9QZR5

F

Seeded From UniProt

complete

MOUSE:HIPK2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:O35625
PR:P02340

F

Seeded From UniProt

complete

MOUSE:AXIN1

GO:0045860: positive regulation of protein kinase activity

ECO:0000314:

P

Figures 4,6,8: Axin activates HIPK2 (homeodomain-interacting protein kinase-2)-mediated p53 phosphorylation and p53-dependent transcription and apoptosis.

complete
CACAO 3582

MOUSE:AXIN1

involved_in

GO:0045860: positive regulation of protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AXIN1

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9QZR5

F

Seeded From UniProt

complete

MOUSE:AXIN1

enables

GO:0002039: p53 binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P02340

F

Seeded From UniProt

complete


See also

References

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