Gene wiki reviewKrüppel-like factor 4 (KLF4): What we currently know
Introduction
The Krüppel-like factor 4 (KLF4; also called gut-enriched Krüppel-like factor or GKLF) was first isolated by Shields et al., from a NIH3T3 cDNA library (Shields et al., 1996). KLF4 gene is conserved among vertebrate species from zebrafish to human (Table 1). In recent years, KLF4 has gained notoriety not only due to its diverse functions in physiology and diseases but to its role as one of four key factors required for inducing pluripotent stem cells. In this article, we review the current understanding of the functions of KLF4.
Section snippets
Structure
KLF4 belongs to the family of SP/KLF factors that are characterized by three zinc finger motifs within their carboxyl terminal sequences (Dang et al., 2000). Within its amino terminus, KLF4 possess a transactivation domain (TAD) and adjacent to it, a repression domain, together of which determine the specificity of KLF4’s transcriptional regulating activity by interacting with other factors and modulating DNA binding efficiency (Fig. 1) (Geiman et al., 2000, Yet et al., 1998). Two nuclear
Intestine
KLF4 was originally identified as a gut-enriched transcription factor in the intestine (Shields et al., 1996). Further studies on intestinal tissue localize its expression to the post-mitotic, terminally differentiated columnar intestinal epithelial cells (Ghaleb et al., 2011, McConnell et al., 2007, Flandez et al., 2008). In the intestinal epithelium, KLF4 plays several important roles in regulating intestinal epithelial homeostasis. For example, KLF4 has a critical role in the development and
Development and progression of cancer/EMT
KLF4 expression is frequently lost in various human cancer types, such as colorectal cancer, gastric cancer, esophageal squamous cell carcinoma, prostate cancer, and bladder cancer (Wei et al., 2005, Zhang et al., 2012a, Zhao et al., 2004, Ton-That et al., 1997, Schulz and Hatina, 2006, Ohnishi et al., 2003). KLF4 was shown to undergo promoter methylation and loss of heterozygosity in gastrointestinal cancer (Wei et al., 2005). Consistent with its tumor-suppressive function, overexpression of
Stem cells
The importance of KLF4 as a stemness factor first came in the spotlight from the work of Takahashi and Yamanaka in 2006, when they demonstrated for the first time that, under specific culture conditions, mouse embryonic and adult fibroblasts can be induced into pluripotent stem cells by overexpressing four specific factors: Oct3/4, Sox2, Myc, and Klf4 (Takahashi & Yamanaka, 2006). This was later replicated using adult human fibroblasts (Takahashi et al., 2007). These initial publications opened
Concluding remarks
Recent studies on KLF4 have continued to expand our knowledge of its diverse functions and essential roles in numerous tissues/organs and cellular processes. A common theme is that KLF4 has a context-dependent function, under certain conditions KLF4 would undergo a certain role, while under different conditions it may play a completely opposite role. This highlights the critical role of different factors that interact with KLF4 and those which dictate what role it plays, and when. Thus, we
Conflict of interest
No conflicts of interest, financial or otherwise, are declared by the authors.
Acknowledgments
This review and the corresponding Gene Wiki article are written as part of the Gene Wiki Review series–a series resulting from a collaboration between the journal GENE and the Gene Wiki Initiative. The Gene Wiki Initiative is supported by National Institutes of Health (GM089820). Additional support for Gene Wiki Reviews is provided by Elsevier, the publisher of GENE. The authors would like to thank Dr. Agnieszka Bialkowska for her excellent assistance in revising and proofing the manuscript.
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