Shaking the family tree: identification of novel and biologically active alternatively spliced isoforms across the KLF family of transcription factors

Abstract

Alternative splicing represents a unique post-transcriptional mechanism that increases the complexity of the eukaryotic proteome-generating protein isoforms whose functions can be novel, diverse, and/or even antagonistic when compared to its full-length transcript. The KLF family of genes consists of ≥17 members, which are involved in the regulation of numerous critical cellular processes, including differentiation, cell proliferation, growth-related signal transduction, angiogenesis, and apoptosis. Using a strategy based on RT-PCR, selective cloning, and promoter-based assays of cancer-relevant genes, we identify and characterize the existence of multiple biologically active KLF splice forms across the entire family of proteins. We demonstrate biological function for a number of these isoforms. Furthermore, we highlight a possible functional interaction between full-length KLF4 and one of its splice variants in up-regulating cellular proliferation. Taken together, this report identifies for the first time a more complete view of the genomic and proteomic breadth and complexity of the KLF transcription factor family, revealing the existence of highly expressed and biologically active isoforms previously uncharacterized. In essence, knowing that these KLF isoforms exist provides the first step toward understanding the roles of these genes in human health and disease.

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

“…The transcriptional activity of KLF4 is also regulated by a number of posttranslational modifications, such as glycosylation, ubiquitination, sumoylation, acetylation, and phosphorylation (5). Finally, alternative splice variants exist for KLF4, including KLF4␣, which alters transcriptional activity as a dominant negative (5,74,75). We detected KLF4␣ expression in most leukemia cell lines and in healthy normal bone marrow (data not shown) (74), suggesting that altered splicing may not regulate KLF4 in myeloid leukemias.…”

Krüppel-like factor 4 (KLF4): What we currently know

“…Several splicing variants of the human KLF4 gene have been identified in normal and cancer cells (e.g. human pancreatic cancer cells; Figure 2) (6–8). …”

The Krüppel-like factors in female reproductive system pathologies

“…We refer the reader to recent excellent reviews on this family (Tetrault et al ., 2013; Knoedler & Denver, 2014; Limame et al , 2014), which now also includes multiple biologically active KLF splice isoforms (Camacho-Venegas et al ., 2013) and the related gene KLF18 that is present in the sequenced genomes of most placental mammals (Pei & Grishin, 2013). KLF proteins are characterized by a conserved DNA-binding domain with three tandem C 2 H 2 -type zinc finger motifs at the carboxy-terminus and which recognizes the GT/GC box or CACCC element sites in promoter/5′ regulatory and enhancer regions (Fig.…”