Silencing of the transforming growth factor-beta (TGFbeta) receptor II by Kruppel-like factor 14 underscores the importance of a negative feedback mechanism in TGFbeta signaling.
The role of non-Smad proteins in the regulation of transforming growth factor-beta (TGFbeta) signaling is an emerging line of active investigation. Here, we characterize the role of KLF14, as a TGFbeta-inducible, non-Smad protein that silences the TGFbeta receptor II (TGFbetaRII) promoter. Together with endocytosis, transcriptional silencing is a critical mechanism for down-regulating TGFbeta 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 TGFbeta inducibility, its ability to regulate the TGFbetaRII promoter, and the fact that this protein had yet to be functionally characterized. We find that KLF14 represses the TGFbetaRII, a function that is augmented by TGFbeta treatment. Mapping of the TGFbetaRII 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 TGFbetaRII promoter via a co-repressor complex containing mSin3A and HDAC2. Furthermore, the TGFbeta pathway activation leads to recruitment of a KLF14-mSin3A-HDAC2 repressor complex to the TGFbetaRII 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 TGFbetaRII activation at the cell surface induces the expression of KLF14 to ultimately silence the TGFbetaRII and further expand the network of non-Smad transcription factors that participate in the TGFbeta pathway.
Truty
Mark J
MJ
Department of Biochemistry and Molecular Biology, Gastroenterology Research Unit, Mayo Clinic, Rochester, MN 55905, USA.
Lomberk
Gwen
G
Fernandez-Zapico
Martin E
ME
Urrutia
Raul
R
D045744:Cell Line, Tumor; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology*; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051703:Sp Transcription Factors; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
D006657:Histones; C417549:KLF14 protein, human; D051741:Kruppel-Like Transcription Factors; D046912:Multiprotein Complexes; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins; D051703:Sp Transcription Factors; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases