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PMID:9703499

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Citation

Carballo, E, Lai, WS and Blackshear, PJ (1998) Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science 281:1001-5

Abstract

Tumor necrosis factor-alpha (TNF-alpha) is a major mediator of both acute and chronic inflammatory responses in many diseases. Tristetraprolin (TTP), the prototype of a class of Cys-Cys-Cys-His (CCCH) zinc finger proteins, inhibited TNF-alpha production from macrophages by destabilizing its messenger RNA. This effect appeared to result from direct TTP binding to the AU-rich element of the TNF-alpha messenger RNA. TTP is a cytosolic protein in these cells, and its biosynthesis was induced by the same agents that stimulate TNF-alpha production, including TNF-alpha itself. These findings identify TTP as a component of a negative feedback loop that interferes with TNF-alpha production by destabilizing its messenger RNA. This pathway represents a potential target for anti-TNF-alpha therapies.

Links

PubMed

Keywords

3T3 Cells; Animals; Base Sequence; Biological Transport; Cell Line; Cell Nucleus/metabolism; Chick Embryo; Cytosol/metabolism; DNA-Binding Proteins; Feedback; Gene Expression Regulation; Humans; Immediate-Early Proteins; Lipopolysaccharides/pharmacology; Macrophages/physiology; Mice; Mice, Knockout; Proteins/physiology; RNA Probes; RNA, Messenger/chemistry; RNA, Messenger/genetics; RNA, Messenger/metabolism; Transfection; Tristetraprolin; Tumor Necrosis Factor-alpha/antagonists & inhibitors; Tumor Necrosis Factor-alpha/biosynthesis; Tumor Necrosis Factor-alpha/genetics; Zinc Fingers

Significance

Annotations

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

MOUSE:TTP

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TTP

involved_in

GO:0071356: cellular response to tumor necrosis factor

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TTP

involved_in

GO:0071222: cellular response to lipopolysaccharide

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TTP

located_in

GO:0005737: cytoplasm

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TTP

involved_in

GO:0006402: mRNA catabolic process

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TTP

part_of

GO:0005737: cytoplasm

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TTP

enables

GO:0035925: mRNA 3'-UTR AU-rich region binding

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TTP

involved_in

GO:0043488: regulation of mRNA stability

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TTP

enables

GO:0035925: mRNA 3'-UTR AU-rich region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TTP

involved_in

GO:0061158: 3'-UTR-mediated mRNA destabilization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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