Silencing of the transforming growth factor-β (TGFβ) receptor II by Krüppel-like factor 14 underscores the importance of a negative feedback mechanism in TGFβ signaling

Mark Truty, Gwen Lomberk, Martin E Fernandez-Zapico, Raul Urrutia

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36 Citations (Scopus)

Abstract

The role of non-Smad proteins in the regulation of transforming growth factor-β (TGFβ) signaling is an emerging line of active investigation. Here, we characterize the role of KLF14, as a TGFβ-inducible, non-Smad protein that silences the TGFβ receptor II (TGFβRII) promoter. Together with endocytosis, transcriptional silencing is a critical mechanism for down-regulating TGFβ receptors at the cell surface. However, the mechanisms underlying transcriptional repression of these receptors remain poorly understood. KLF14 has been chosen from a comprehensive screen of 24 members of the Sp/KLF family due to its TGFβ inducibility, its ability to regulate the TGFβRII promoter, and the fact that this protein had yet to be functionally characterized. We find that KLF14 represses the TGFβRII, a function that is augmented by TGFβ treatment. Mapping of the TGFβRII promoter, in combination with site-directed mutagenesis, electromobility shift, and chromatin immunoprecipitation assays, have identified distinct GC-rich sequences used by KLF14 to regulate this promoter. Mechanistically, KLF14 represses the TGFβRII promoter via a co-repressor complex containing mSin3A and HDAC2. Furthermore, the TGFβ pathway activation leads to recruitment of a KLF14-mSin3A-HDAC2 repressor complex to the TGFβRII promoter, as well as the remodeling of chromatin to increase histone marks that associate with transcriptional silencing. Thus, these results describe a novel negative-feedback mechanism by which TGFβRII activation at the cell surface induces the expression of KLF14 to ultimately silence the TGFβRII and further expand the network of non-Smad transcription factors that participate in the TGFβ pathway.

Original languageEnglish (US)
Pages (from-to)6291-6300
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number10
DOIs
StatePublished - Mar 6 2009

Fingerprint

Growth Factor Receptors
Transforming Growth Factors
Feedback
Chromatin
Histone Code
Chemical activation
GC Rich Sequence
Co-Repressor Proteins
Mutagenesis
Proteins
Chromatin Assembly and Disassembly
Chromatin Immunoprecipitation
Site-Directed Mutagenesis
Endocytosis
Histones
Assays
Transcription Factors

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

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title = "Silencing of the transforming growth factor-β (TGFβ) receptor II by Kr{\"u}ppel-like factor 14 underscores the importance of a negative feedback mechanism in TGFβ signaling",
abstract = "The role of non-Smad proteins in the regulation of transforming growth factor-β (TGFβ) signaling is an emerging line of active investigation. Here, we characterize the role of KLF14, as a TGFβ-inducible, non-Smad protein that silences the TGFβ receptor II (TGFβRII) promoter. Together with endocytosis, transcriptional silencing is a critical mechanism for down-regulating TGFβ receptors at the cell surface. However, the mechanisms underlying transcriptional repression of these receptors remain poorly understood. KLF14 has been chosen from a comprehensive screen of 24 members of the Sp/KLF family due to its TGFβ inducibility, its ability to regulate the TGFβRII promoter, and the fact that this protein had yet to be functionally characterized. We find that KLF14 represses the TGFβRII, a function that is augmented by TGFβ treatment. Mapping of the TGFβRII promoter, in combination with site-directed mutagenesis, electromobility shift, and chromatin immunoprecipitation assays, have identified distinct GC-rich sequences used by KLF14 to regulate this promoter. Mechanistically, KLF14 represses the TGFβRII promoter via a co-repressor complex containing mSin3A and HDAC2. Furthermore, the TGFβ pathway activation leads to recruitment of a KLF14-mSin3A-HDAC2 repressor complex to the TGFβRII promoter, as well as the remodeling of chromatin to increase histone marks that associate with transcriptional silencing. Thus, these results describe a novel negative-feedback mechanism by which TGFβRII activation at the cell surface induces the expression of KLF14 to ultimately silence the TGFβRII and further expand the network of non-Smad transcription factors that participate in the TGFβ pathway.",
author = "Mark Truty and Gwen Lomberk and Fernandez-Zapico, {Martin E} and Raul Urrutia",
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T1 - Silencing of the transforming growth factor-β (TGFβ) receptor II by Krüppel-like factor 14 underscores the importance of a negative feedback mechanism in TGFβ signaling

AU - Truty, Mark

AU - Lomberk, Gwen

AU - Fernandez-Zapico, Martin E

AU - Urrutia, Raul

PY - 2009/3/6

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N2 - The role of non-Smad proteins in the regulation of transforming growth factor-β (TGFβ) signaling is an emerging line of active investigation. Here, we characterize the role of KLF14, as a TGFβ-inducible, non-Smad protein that silences the TGFβ receptor II (TGFβRII) promoter. Together with endocytosis, transcriptional silencing is a critical mechanism for down-regulating TGFβ receptors at the cell surface. However, the mechanisms underlying transcriptional repression of these receptors remain poorly understood. KLF14 has been chosen from a comprehensive screen of 24 members of the Sp/KLF family due to its TGFβ inducibility, its ability to regulate the TGFβRII promoter, and the fact that this protein had yet to be functionally characterized. We find that KLF14 represses the TGFβRII, a function that is augmented by TGFβ treatment. Mapping of the TGFβRII promoter, in combination with site-directed mutagenesis, electromobility shift, and chromatin immunoprecipitation assays, have identified distinct GC-rich sequences used by KLF14 to regulate this promoter. Mechanistically, KLF14 represses the TGFβRII promoter via a co-repressor complex containing mSin3A and HDAC2. Furthermore, the TGFβ pathway activation leads to recruitment of a KLF14-mSin3A-HDAC2 repressor complex to the TGFβRII promoter, as well as the remodeling of chromatin to increase histone marks that associate with transcriptional silencing. Thus, these results describe a novel negative-feedback mechanism by which TGFβRII activation at the cell surface induces the expression of KLF14 to ultimately silence the TGFβRII and further expand the network of non-Smad transcription factors that participate in the TGFβ pathway.

AB - The role of non-Smad proteins in the regulation of transforming growth factor-β (TGFβ) signaling is an emerging line of active investigation. Here, we characterize the role of KLF14, as a TGFβ-inducible, non-Smad protein that silences the TGFβ receptor II (TGFβRII) promoter. Together with endocytosis, transcriptional silencing is a critical mechanism for down-regulating TGFβ receptors at the cell surface. However, the mechanisms underlying transcriptional repression of these receptors remain poorly understood. KLF14 has been chosen from a comprehensive screen of 24 members of the Sp/KLF family due to its TGFβ inducibility, its ability to regulate the TGFβRII promoter, and the fact that this protein had yet to be functionally characterized. We find that KLF14 represses the TGFβRII, a function that is augmented by TGFβ treatment. Mapping of the TGFβRII promoter, in combination with site-directed mutagenesis, electromobility shift, and chromatin immunoprecipitation assays, have identified distinct GC-rich sequences used by KLF14 to regulate this promoter. Mechanistically, KLF14 represses the TGFβRII promoter via a co-repressor complex containing mSin3A and HDAC2. Furthermore, the TGFβ pathway activation leads to recruitment of a KLF14-mSin3A-HDAC2 repressor complex to the TGFβRII promoter, as well as the remodeling of chromatin to increase histone marks that associate with transcriptional silencing. Thus, these results describe a novel negative-feedback mechanism by which TGFβRII activation at the cell surface induces the expression of KLF14 to ultimately silence the TGFβRII and further expand the network of non-Smad transcription factors that participate in the TGFβ pathway.

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