An mSin3A interaction domain links the transcriptional activity of KLF11 with its role in growth regulation.
KLF11 is a biochemical paradigm for a subset of proteins that repress transcription via a Mad1-like mSin3A interacting domain (SID). The biological role of these proteins and the significance of their biochemical activity, however, remain to be established. We report that KLF11 is downregulated in human cancers, inhibits cell growth in vitro and in vivo, and suppresses neoplastic transformation. Transgenic mice for KLF11 display a downregulation of genes encoding the oxidative stress scavengers SOD2 and Catalase1. Chromatin immunoprecipitation assays confirm that, indeed, these genes are bonafide targets of KLF11. KLF11 expression renders cells more sensitive to oxidative drugs, an effect that is rescued by infection with recombinant adenoviruses expressing SOD2 and Catalase1. KLF11-regulated functions require the Mad1-like SID, indicating that these target genes involved in these phenomena are regulated via this corepressor system. These results demonstrate that SID-containing KLF repressor proteins can inhibit cell growth and neoplastic transformation, and outline for the first time cellular and molecular mechanisms by which these functions may be achieved.
Fernandez-Zapico
Martin E
ME
Gastroenterology Research Unit, Saint Mary's Hospital, Mayo Clinic, Rochester, MN 55905, USA.
Mladek
Ann
A
Ellenrieder
Volker
V
Folch-Puy
Emma
E
Miller
Laurence
L
Urrutia
Raul
R
D016475:3T3 Cells; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D016466:CHO Cells; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002455:Cell Division; D006224:Cricetinae; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; C115117:KLF11 protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D014157:Transcription Factors; D056264:Sin3 Histone Deacetylase and Corepressor Complex