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PMID:10751406

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Citation

Lai, WS, Carballo, E, Thorn, JM, Kennington, EA and Blackshear, PJ (2000) Interactions of CCCH zinc finger proteins with mRNA. Binding of tristetraprolin-related zinc finger proteins to Au-rich elements and destabilization of mRNA. J. Biol. Chem. 275:17827-37

Abstract

Macrophages derived from tristetraprolin (TTP)-deficient mice exhibited increased tumor necrosis factor alpha (TNFalpha) release as a consequence of increased stability of TNFalpha mRNA. TTP was then shown to destabilize TNFalpha mRNA after binding directly to the AU-rich region (ARE) of the 3'-untranslated region of the TNFalpha mRNA. In mammals and in Xenopus, TTP is the prototype of a small family of three known zinc finger proteins containing two CCCH zinc fingers spaced 18 amino acids apart; a fourth more distantly related family member has been identified in Xenopus and fish. We show here that representatives of all four family members were able to bind to the TNFalpha ARE in a cell-free system and, in most cases, promote the breakdown of TNFalpha mRNA in intact cells. Because the primary sequences of these CCCH proteins are most closely related in their tandem zinc finger domains, we tested whether various fragments of TTP that contained both zinc fingers resembled the intact protein in these assays. We found that amino- and carboxyl-terminal truncated forms of TTP, as well as a 77 amino acid fragment that contained both zinc fingers, could bind to the TNFalpha ARE in cell-free cross-linking and gel shift assays. In addition, these truncated forms of TTP could also stimulate the apparent deadenylation and/or breakdown of TNFalpha mRNA in intact cells. Alignments of the tandem zinc finger domains from all four groups of homologous proteins have identified invariant residues as well as group-specific signature amino acids that presumably contribute to ARE binding and protein-specific activities, respectively.

Links

PubMed Online version:10.1074/jbc.M001696200

Keywords

3' Untranslated Regions/chemistry; 3' Untranslated Regions/metabolism; Amino Acid Sequence; Animals; Base Sequence; Cell Line; DNA-Binding Proteins; Evolution, Molecular; Humans; Immediate-Early Proteins; Membrane Proteins/chemistry; Membrane Proteins/metabolism; Mice; Molecular Sequence Data; Peptide Termination Factors/chemistry; Peptide Termination Factors/metabolism; Phylogeny; Proteins/chemistry; Proteins/metabolism; RNA, Messenger/chemistry; RNA, Messenger/metabolism; Recombinant Proteins/chemistry; Recombinant Proteins/metabolism; Saccharomyces cerevisiae Proteins; Sequence Alignment; Sequence Homology, Amino Acid; Transfection; Tristetraprolin; Xenopus; Xenopus Proteins; Zinc Fingers

Significance

Annotations

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

RAT:TISB

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:TISB

acts_upstream_of_or_within

GO:0006402: mRNA catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:TISB

enables

GO:0003729: mRNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:TISB

enables

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

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:TTP

located_in

GO:0005829: cytosol

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P26651

C

Seeded From UniProt

complete

MOUSE:TTP

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:TTP

acts_upstream_of_or_within

GO:0006402: mRNA catabolic process

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P26651

P

Seeded From UniProt

complete

MOUSE:TTP

enables

GO:0003729: mRNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:TISB

located_in

GO:0005829: cytosol

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P17431

C

Seeded From UniProt

complete

MOUSE:TISB

acts_upstream_of_or_within

GO:0006402: mRNA catabolic process

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P17431

P

Seeded From UniProt

complete

MOUSE:TISB

enables

GO:0003729: mRNA binding

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P17431

F

Seeded From UniProt

complete

HUMAN:TTP

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TTP

acts_upstream_of_or_within

GO:0006402: mRNA catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TTP

involved_in

GO:0006402: mRNA catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TTP

part_of

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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