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PMID:17242187

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Citation

Song, L, Li, J, Ye, J, Yu, G, Ding, J, Zhang, D, Ouyang, W, Dong, Z, Kim, SO and Huang, C (2007) p85alpha acts as a novel signal transducer for mediation of cellular apoptotic response to UV radiation. Mol. Cell. Biol. 27:2713-31

Abstract

Apoptosis is an important cellular response to UV radiation (UVR), but the corresponding mechanisms remain largely unknown. Here we report that the p85alpha regulatory subunit of phosphatidylinositol 3-kinase (PI-3K) exerted a proapoptotic role in response to UVR through the induction of tumor necrosis factor alpha (TNF-alpha) gene expression. This special effect of p85alpha was unrelated to the PI-3K-dependent signaling pathway. Further evidence demonstrated that the inducible transcription factor NFAT3 was the major downstream target of p85alpha for the mediation of UVR-induced apoptosis and TNF-alpha gene transcription. p85alpha regulated UVR-induced NFAT3 activation by modulation of its nuclear translocation and DNA binding and the relevant transcriptional activities. Gel shift assays and site-directed mutagenesis allowed the identification of two regions in the TNF-alpha gene promoter that served as the NFAT3 recognition sequences. Chromatin immunoprecipitation assays further confirmed that the recruitment of NFAT3 to the endogenous TNF-alpha promoter was regulated by p85alpha upon UVR exposure. Finally, the knockdown of the NFAT3 level by its specific small interfering RNA decreased UVR-induced TNF-alpha gene transcription and cell apoptosis. The knockdown of endogenous p85alpha blocked NFAT activity and TNF-alpha gene transcription, as well as cell apoptosis. Thus, we demonstrated p85alpha-associated but PI-3K-independent cell death in response to UVR and identified a novel p85alpha/NFAT3/TNF-alpha signaling pathway for the mediation of cellular apoptotic responses under certain stress conditions such as UVR.

Links

PubMed PMC1899908 Online version:10.1128/MCB.00657-06

Keywords

Active Transport, Cell Nucleus; Animals; Apoptosis; Cell Nucleus/metabolism; Cells, Cultured; Fibroblasts/metabolism; Gene Expression Regulation; Mice; Mice, Knockout; Mutagenesis, Site-Directed; Mutation; NFATC Transcription Factors/genetics; NFATC Transcription Factors/physiology; Phosphatidylinositol 3-Kinases/genetics; Phosphatidylinositol 3-Kinases/physiology; Promoter Regions, Genetic; Protein Subunits/genetics; Protein Subunits/physiology; Signal Transduction; Tumor Necrosis Factor-alpha/genetics; Tumor Necrosis Factor-alpha/physiology; Ultraviolet Rays

Significance

Annotations

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

MOUSE:TNFA

acts_upstream_of_or_within

GO:0008630: intrinsic apoptotic signaling pathway in response to DNA damage

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:TNR1A

acts_upstream_of_or_within

GO:0008630: intrinsic apoptotic signaling pathway in response to DNA damage

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:TNR1B

acts_upstream_of_or_within

GO:0008630: intrinsic apoptotic signaling pathway in response to DNA damage

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:P85A

acts_upstream_of_or_within

GO:0034644: cellular response to UV

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2149414

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:P85A

acts_upstream_of_or_within

GO:0034644: cellular response to UV

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103296

P

  • occurs_in:(CL:0000057)|occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:P85A

acts_upstream_of_or_within

GO:0032760: positive regulation of tumor necrosis factor production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:P85A

acts_upstream_of_or_within

GO:0008630: intrinsic apoptotic signaling pathway in response to DNA damage

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2149414

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:P85A

acts_upstream_of_or_within

GO:0008630: intrinsic apoptotic signaling pathway in response to DNA damage

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:104798

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:P85A

acts_upstream_of_or_within

GO:0006606: protein import into nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2149414

P

  • occurs_in:(CL:0000057)
  • has_input:(MGI:MGI:1920431)

Seeded From UniProt

complete

MOUSE:P85A

acts_upstream_of_or_within

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

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2149414

P

  • regulates_o_occurs_in:(CL:0000057)
  • has_input:(MGI:MGI:104798)

Seeded From UniProt

complete

MOUSE:NFAC4

acts_upstream_of_or_within

GO:0034644: cellular response to UV

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97583

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:NFAC4

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:NFAC4

acts_upstream_of_or_within

GO:0032760: positive regulation of tumor necrosis factor production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:NFAC4

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:NFAC4

acts_upstream_of_or_within

GO:0008630: intrinsic apoptotic signaling pathway in response to DNA damage

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:NFAC4

acts_upstream_of_or_within

GO:0008630: intrinsic apoptotic signaling pathway in response to DNA damage

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97583

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:NFAC4

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0000057)
  • has_input:(MGI:MGI:104798)

Seeded From UniProt

complete

MOUSE:NFAC4

enables

GO:0000981: DNA-binding transcription factor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0000057)
  • has_input:(MGI:MGI:104798)

Seeded From UniProt

complete

MOUSE:NFAC4

acts_upstream_of_or_within

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000057)
  • has_input:(MGI:MGI:104798)

Seeded From UniProt

complete

MOUSE:TNFA

acts_upstream_of_or_within

GO:0008630: intrinsic apoptotic signaling pathway in response to DNA damage

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:P85A

acts_upstream_of_or_within

GO:0034644: cellular response to UV

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103296

P

occurs_in:(CL:0000057)|occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:P85A

acts_upstream_of_or_within

GO:0034644: cellular response to UV

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2149414

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:P85A

acts_upstream_of_or_within

GO:0032760: positive regulation of tumor necrosis factor production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:P85A

acts_upstream_of_or_within

GO:0008630: intrinsic apoptotic signaling pathway in response to DNA damage

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:104798

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:P85A

acts_upstream_of_or_within

GO:0008630: intrinsic apoptotic signaling pathway in response to DNA damage

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2149414

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:P85A

acts_upstream_of_or_within

GO:0006606: protein import into nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2149414

P

  • occurs_in:(CL:0000057)
  • has_direct_input:(MGI:MGI:1920431)

Seeded From UniProt

complete

MOUSE:P85A

acts_upstream_of_or_within

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

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2149414

P

  • regulates_o_occurs_in:(CL:0000057)
  • has_regulation_target:(MGI:MGI:104798)

Seeded From UniProt

complete


See also

References

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