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PMID:15688372

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Citation

Park, MY, Ryu, SW, Kim, KD, Lim, JS, Lee, ZW and Kim, E (2005) Fas-associated factor-1 mediates chemotherapeutic-induced apoptosis via death effector filament formation. Int. J. Cancer 115:412-8

Abstract

Fas-associated factor-1 (FAF1) is a newly introduced member of the Fas death-inducing signaling complex and potentiates Fas-mediated apoptosis. Clinical study has revealed that FAF1 is significantly reduced in gastric carcinomas. The present study demonstrates that FAF1 mediates chemotherapeutic-induced apoptosis via participation in the formation of death effector filament (DEF), a cytoskeleton-like structure found in receptor-independent apoptosis. Overexpression of FAF1 enhanced DEF assembly and cell death induced by chemotherapeutics such as staurosporine (STS), cisplatin (CDDP) and etoposide (VP16). FAF1 sensitized cells to STS, CDDP and VP16 in dose- and time-dependent manner. Introduction of antisense FAF1 construct inhibited DEF assembly and chemotherapeutic-induced apoptosis. Analysis using FAF1 truncates showed that the FAF1 domain interacting with DEDs of FADD and caspase-8 was sufficient to enhance DEF assembly. Confocal microscopy revealed that FAF1 was present in DEFs together with FADD and caspase-8. Collectively, our data provide a molecular mechanism for the chemosensitization by FAF1 (i.e., mediating DEF assembly).

Links

PubMed Online version:10.1002/ijc.20857

Keywords

Adaptor Proteins, Signal Transducing/metabolism; Antineoplastic Agents/pharmacology; Antineoplastic Agents, Phytogenic/pharmacology; Apoptosis/drug effects; Carrier Proteins/antagonists & inhibitors; Carrier Proteins/genetics; Carrier Proteins/metabolism; Caspase 8; Caspases/metabolism; Cisplatin/pharmacology; DNA, Antisense/pharmacology; Drug Resistance, Neoplasm; Enzyme Inhibitors/pharmacology; Etoposide/pharmacology; Fas-Associated Death Domain Protein; HeLa Cells; Humans; Staurosporine/pharmacology

Significance

Annotations

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

HUMAN:DEDD

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UNN5

F

Seeded From UniProt

complete

HUMAN:FADD

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UNN5

F

Seeded From UniProt

complete

HUMAN:FAF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75618

F

Seeded From UniProt

complete

HUMAN:FAF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13158

F

Seeded From UniProt

complete

HUMAN:FAF1

involved_in

GO:0031334: positive regulation of protein-containing complex assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FAF1

involved_in

GO:0031334: positive regulation of protein complex assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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