TIEG proteins join the Smads as TGF-β-regulated transcription factors that control pancreatic cell growth

Abstract

The control of epithelial cell proliferation, differentiation, and apoptosis requires a balance between signaling and transcriptional regulation. Recent developments in pancreatic cell research have revealed that transforming growth factor-beta (TGF-beta) signaling is important for the regulation of each of these phenomena. More importantly, perturbations in this pathway are associated with pancreatic cancer. A chief example of these alterations is the mutation in the TGF-beta-regulated transcription factor Smad4/DPC4 that is found in a large percentage of pancreatic tumors. Surprisingly, studies on transcription factors have remained an underrepresented area of pancreatic research. However, the discovery of Smad4/DPC4 as a transcription factor fueled further studies aimed at characterizing transcription factors involved in normal and neoplastic pancreatic cell growth. Our laboratory recently described the existence of a novel family of zinc finger transcription factors, TGF-beta-inducible early-response gene (TIEG)1 and TIEG2, from the exocrine pancreas that, similarly to Smads, participate in the TGF-beta response and inhibit epithelial cell proliferation. This review therefore focuses on describing the structure and function of these two families of transcription factor proteins that are becoming key players in the regulation of pancreatic cell growth.

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).…”

“…Based on previous findings demonstrating that the zinc finger transcription factor KLF11 is highly induced by TGFh and, when overexpressed, mimics a TGFh-induced cell cycle arrest in epithelial cells, it has long been suspected that KLF11 might be a downstream effector of TGFh in cell growth control (12,15). 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).…”

“…There is increasing evidence that a group of transcriptional repressors, which are themselves inducible by TGFh signaling, may play an important part in TGFh-mediated gene silencing (12)(13)(14)(15). 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).…”

Krüppel-like Factors: Three Fingers in Many Pies

“…First, investigation of TGF-␤-driven effects on pancreatic epithelia, prostate, and brain cell growth led to the identification of KLF10/ TIEG1/EGR␣ and KLF11/TIEG2/FKLF (14). These two proteins are not only most homologous with each other (Fig.…”

“…1, subgroup 2), but they are also immediate-early TGF-␤-responsive genes that behave as potent repressors via three uniquely conserved repression motifs (15). Overexpression of KLF10 or -11 in a pancreatic cell line or in transgenic mice reveals that the functional effect of this repression is inhibition of cell growth (14) and induction of apoptosis via formation of reactive oxygen species (16). Second, KLF4/ GKLF is directly induced by IFN␥ in a human colon carcinoma cell line, as mRNA induction is rapid and occurs in the absence of protein synthesis (17).…”