An mSin3A interaction domain links the transcriptional activity of KLF11 with its role in growth regulation

Abstract

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 signi®cance 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 con®rm that, indeed, these genes are bona®de 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 ®rst time cellular and molecular mechanisms by which these functions may be achieved.

The Tumor Suppressor KLF11 Mediates a Novel Mechanism in Transforming Growth Factor β–Induced Growth Inhibition That Is Inactivated in Pancreatic Cancer

“…Additional support for this hypothesis was gathered by more recent investigations, which proposed a link between KLF11-regulated gene expression and the capacity of TGFh to suppress cell proliferation (13,15,16). We and others have shown, for instance, that KLF11-induced growth inhibition requires the ability to repress gene expression, and that KLF11, via down-regulation of the inhibitory Smad7 protein, increases TGFh-induced gene transcription in TGFh-sensitive epithelial cells, but not in pancreatic cancer cells (13,17,18). However, neither of the previous studies provided evidence for a direct role of KLF11 in TGFh-mediated control of growth-regulating genes, nor have the underlying molecular mechanisms in KLF11-induced growth inhibition been studied in detail.…”

“…One of these is KLF11 (also termed TIEG2 or FKLF), a zinc finger protein which is ubiquitously expressed in human tissues, with the highest levels found in healthy pancreas (13). When artificially overexpressed in carcinoma cell lines, KLF11 has been shown to exert tumor suppressor functions through its potential to suppress epithelial cell growth (16,17). First evidence for a role of KLF11 in TGFh-regulated gene expression was recently presented by our group, demonstrating that KLF11 potentiates Smad-signaling activity through termination of the negative feedback loop imposed by Smad7 (18).…”

Human Krüppel-like factor 11 inhibits human proinsulin promoter activity in pancreatic beta cells

“…These domains have been demonstrated to repress transcription activity [4,5]. In this sense, KLF11 acts as a dominant repressor of the caveolin-1 gene [13] and, besides its negative regulation of cell growth in the exocrine pancreas [9], KLF11 overexpression also inhibits cell proliferation in Chinese hamster ovary cells [6]. KLF11 further suppressed oncogene-induced neoplastic transformation in mouse NIH-3T3 cells, and consequently KLF11 mRNA expression was found to be significantly downregulated in a substantial amount (50%) of investigated pancreatic, breast and kidney tumours [9].…”

“…In this sense, KLF11 acts as a dominant repressor of the caveolin-1 gene [13] and, besides its negative regulation of cell growth in the exocrine pancreas [9], KLF11 overexpression also inhibits cell proliferation in Chinese hamster ovary cells [6]. KLF11 further suppressed oncogene-induced neoplastic transformation in mouse NIH-3T3 cells, and consequently KLF11 mRNA expression was found to be significantly downregulated in a substantial amount (50%) of investigated pancreatic, breast and kidney tumours [9]. In this context, TGF-β inhibits growth of epithelial cells by activation of Smad signalling, which is potentiated through TGF-β-induced KLF11 by termination of the negative feedback loop imposed by Smad7 [14].…”

“…Within the pancreas KLF11 has been described as a negative regulator of exocrine cell proliferation in transgenic mice with acinar cell-specific KLF11 overproduction in vivo and PANC1 epithelial cancer cells overexpressing KLF11 in vitro [9]. As a result, KLF11 transgenic mice develop a significantly smaller exocrine pancreas than controls due to reduced proliferation and enhanced apoptosis.…”