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PMID:14555988

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Citation

Kretschmer, A, Moepert, K, Dames, S, Sternberger, M, Kaufmann, J and Klippel, A (2003) Differential regulation of TGF-beta signaling through Smad2, Smad3 and Smad4. Oncogene 22:6748-63

Abstract

Smad transcription factors mediate the growth inhibitory effect of transforming growth factor-beta (TGF-beta) in many cell types. Mutational inactivation of Smads has been correlated with loss of responsiveness to TGF-beta-mediated signal transduction. In this study, we compare the contribution of individual Smads to TGF-beta-induced growth inhibition and endogenous gene expression in isogenic cellular backgrounds. Smad2, Smad3 and Smad4 expression were selectively inhibited in differentiation-competent cells by using improved antisense molecules. We found that TGF-beta mediates its inhibitory effect on HaCaT keratinocyte cell growth predominantly through Smad3. Inhibition of Smad3 expression was sufficient to interfere with TGF-beta-induced cell cycle arrest and to induce or suppress endogenous cell cycle regulators. Inhibition of Smad4 expression exhibited a partial effect, whereas inhibition of Smad2 expression had no effect. By gene expression profiling, we identified TGF-beta-dependent genes that are differentially regulated by Smad2 and Smad3 under regular growth conditions on a genome-wide scale. We show that Smad2, Smad3 and Smad4 contribute to the regulation of TGF-beta responses to varying extents, and demonstrate, in addition, that these Smads exhibit distinct roles in different cell types.

Links

PubMed Online version:10.1038/sj.onc.1206791

Keywords

Blotting, Western; Cell Cycle; Cell Line; DNA Mutational Analysis; DNA-Binding Proteins/physiology; Down-Regulation; Electrophoresis, Polyacrylamide Gel; Flow Cytometry; Gene Expression Regulation; Humans; Immunoblotting; Oligonucleotide Array Sequence Analysis; Oligonucleotides, Antisense/pharmacology; RNA/metabolism; RNA, Messenger/metabolism; Signal Transduction; Smad2 Protein; Smad3 Protein; Smad4 Protein; Trans-Activators/physiology; Transfection; Transforming Growth Factor beta/biosynthesis; Transforming Growth Factor beta/genetics; Transforming Growth Factor beta/metabolism

Significance

Annotations

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

HUMAN:TGFB1

involved_in

GO:0051726: regulation of cell cycle

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD3

involved_in

GO:0051726: regulation of cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD3

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P38936)|has_input:(UniProtKB:P42772)|has_input:(UniProtKB:P21980)|has_input:(UniProtKB:P09601)|has_input:(UniProtKB:P84022)

Seeded From UniProt

complete

HUMAN:SMAD2

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD2

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD2

involved_in

GO:0017015: regulation of transforming growth factor beta receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD3

involved_in

GO:0007050: cell cycle arrest

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD3

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD3

involved_in

GO:0045930: negative regulation of mitotic cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD3

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_regulation_target:(UniProtKB:P38936)|has_regulation_target:(UniProtKB:P42772)|has_regulation_target:(UniProtKB:P21980)|has_regulation_target:(UniProtKB:P09601)|has_regulation_target:(UniProtKB:P84022)

Seeded From UniProt

complete

HUMAN:TGFB1

involved_in

GO:0045930: negative regulation of mitotic cell cycle

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TGFB1

involved_in

GO:0007050: cell cycle arrest

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TGFB1

involved_in

GO:0035307: positive regulation of protein dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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