Novel Cross Talk of Krüppel-Like Factor 4 and β-Catenin Regulates Normal Intestinal Homeostasis and Tumor Repression

Abstract

Epithelial cells of the intestinal mucosa undergo a continual process of proliferation, differentiation, and apoptosis which is regulated by multiple signaling pathways. The Wnt/␤-catenin pathway plays a critical role in this process. Mutations in the Wnt pathway, however, are associated with colorectal cancers. Krüppel-like factor 4 (KLF4) is an epithelial transcriptional factor that is down-regulated in many colorectal cancers. Here, we show that KLF4 interacts with ␤-catenin and represses ␤-catenin-mediated gene expression. Moreover, KLF4 inhibits the axis formation of Xenopus embryos and inhibits xenograft tumor growth in athymic nude mice. Our findings suggest that the cross talk of KLF4 and ␤-catenin plays a critical role in homeostasis of the normal intestine as well as in tumorigenesis of colorectal cancers.

β-Catenin Regulates Acetylcholine Receptor Clustering in Muscle Cells through Interaction with Rapsyn

“…Wnt, DKK1, and Fz-Fc constructs were described previously (Semenov et al, 2001;Zhang et al, 2006). Stabilized ␤-catenin (␤-cat*) was a gift from Dr. X. Yu (Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China) (Yu and Malenka, 2003).…”

Vaccinia Virus-Mediated Expression of Transcription Factor Klf4 Enhances Oncolytic Virotherapy of Colorectal Cancer

“…Klf4 was located in the cell nucleus, indicating correct protein folding and transportation through the pores of the nuclear membrane. It was demonstrated by Zhang et al [10] that Klf4 interacts with β-catenin protein in the nucleus and inhibits Wnt/β-catenin-mediated signaling and transcription by binding to the transactivation domain [10]. The HT-29 cell line contains two carboxyl terminal-truncated APC proteins instead of a functional APC protein [40] leading to overly abundant intracellular β-catenin levels and increased β-cateninmediated transcription.…”

“…The lower levels of transcription of virally-expressed genes in klf4-expressing rVACV strains correlated with inferior levels of replication ( Figure 3b). Our findings suggest that virus-expressed Klf4 in infected cells is functional and, importantly, that the C-terminal TAT fusion does not interfere with the binding of Klf4 to the C-terminally located trans activation domain of β-catenin [10]. Results are presented as relative percentages of expression in comparison to expression measured in cells infected with GLV-1h68 to account for the effects of rVACV infection alone.…”

“…Klf4 inhibits β-catenin-mediated transcription by binding to the C-terminal transactivating domain of the β-catenin protein [10]. HT-29 cells infected with klf4-expressing rVACVs at a high MOI (5) were analyzed by qPCR ( Figure 2a & Table 1) and ELISA ( Figure 2b) to determine the transcription and expression levels of β-catenin after infection.…”

“…Loss of heterozygosity of the klf4 locus, mutations in open reading frames (ORFs), and hyper methylation of klf4 promoters have been identified in various human CRCs and cell lines [9]. Klf4 also inhibits the transcription of nuclear β-catenin by binding to its C-terminal transactivating domain, implicating the role of Klf4 in the maintenance of intestinal homeostasis and the inhibition of colorectal carcinogenesis [10]. In fact, colorectal cancer lines with low levels of endogenous Klf4 expression exhibited diminished tumorigenicity when induced to express Klf4 [11].…”