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PMID:18460465

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Citation

Komiya, Y, Kurabe, N, Katagiri, K, Ogawa, M, Sugiyama, A, Kawasaki, Y and Tashiro, F (2008) A novel binding factor of 14-3-3beta functions as a transcriptional repressor and promotes anchorage-independent growth, tumorigenicity, and metastasis. J. Biol. Chem. 283:18753-64

Abstract

The 14-3-3 proteins form a highly conserved family of dimeric proteins that interact with various signal transduction proteins and regulate cell cycle, apoptosis, stress response, and malignant transformation. We previously demonstrated that the beta isoform of 14-3-3 proteins promotes tumorigenicity and angiogenesis of rat hepatoma K2 cells. In this study, to analyze the mechanism of 14-3-3beta-induced malignant transformation, yeast two-hybrid screening was performed, and a novel 14-3-3beta-binding factor, FBI1 (fourteen-three-three beta interactant 1), was identified. In vitro binding and co-immunoprecipitation analyses verified specific interaction of 14-3-3beta with FBI1. The strong expression of FBI1 was observed in several tumor cell lines but not in non-tumor cell lines. Forced expression of antisense FBI1 in K2 cells inhibited anchorage-independent growth but had no significant effect on cell proliferation in monolayer culture. Down-regulation of FBI1 also inhibited tumorigenicity and metastasis accompanying a decrease in MMP-9 (matrix metalloproteinase-9) expression. In addition, the duration of ERK1/2 activation was curtailed in antisense FBI1-expressing K2 cells. A luciferase reporter assay revealed that the FBI1-14-3-3beta complex could act as a transcriptional silencer, and MKP-1 (MAPK phosphatase-1) was one of the target genes of the FBI1-14-3-3beta complex. Moreover, chromatin immunoprecipitation analysis demonstrated that FBI1 and 14-3-3beta were presented on the MKP-1 promoter. These results indicate that FBI1 promotes sustained ERK1/2 activation through repression of MKP-1 transcription, resulting in promotion of tumorigenicity and metastasis.

Links

PubMed Online version:10.1074/jbc.M802530200

Keywords

14-3-3 Proteins/genetics; 14-3-3 Proteins/metabolism; Animals; Apoptosis; Base Sequence; Cell Cycle; Cell Line, Tumor; Cell Transformation, Neoplastic/genetics; Cell Transformation, Neoplastic/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Dimerization; Down-Regulation; Dual Specificity Phosphatase 1/biosynthesis; Dual Specificity Phosphatase 1/genetics; Enzyme Activation; Matrix Metalloproteinase 9/genetics; Matrix Metalloproteinase 9/metabolism; Mice; Mice, Inbred BALB C; Mice, Knockout; Mitogen-Activated Protein Kinase 1/genetics; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3/genetics; Mitogen-Activated Protein Kinase 3/metabolism; Molecular Sequence Data; Multiprotein Complexes/genetics; Multiprotein Complexes/metabolism; Neoplasm Metastasis; Neoplasm Proteins/genetics; Neoplasm Proteins/metabolism; Neovascularization, Pathologic/genetics; Neovascularization, Pathologic/metabolism; Promoter Regions, Genetic/genetics; Rats; Rats, Inbred F344; Repressor Proteins/genetics; Repressor Proteins/metabolism; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic/genetics; Two-Hybrid System Techniques

Significance

Annotations

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

HUMAN:1433B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q25C79

F

Seeded From UniProt

complete

RAT:1433B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:1307791

F

Seeded From UniProt

complete

RAT:1433B

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:1433B

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:1433B

part_of

GO:0017053: transcription repressor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:1433B

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:AKIR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:61998

F

Seeded From UniProt

complete

RAT:AKIR2

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:AKIR2

involved_in

GO:0008284: positive regulation of cell population proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:AKIR2

involved_in

GO:0010950: positive regulation of endopeptidase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:AKIR2

involved_in

GO:0010629: negative regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:AKIR2

part_of

GO:0017053: transcription repressor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:AKIR2

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:AKIR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31946

F

Seeded From UniProt

complete

RAT:AKIR2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

See also

References

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