Alternative titles; symbols
HGNC Approved Gene Symbol: KLF5
Cytogenetic location: 13q22.1 Genomic coordinates (GRCh38): 13:73,054,976-73,077,538 (from NCBI)
BTEB1 (602902) is a transcription factor that binds to GC boxes. By screening a placenta library with a rat BTEB1 cDNA, Sogawa et al. (1993) isolated a cDNA encoding BTEB2. The predicted 219-amino acid protein contains 3 consecutive zinc finger motifs near the C terminus. The zinc finger domains were 59% and 64% identical to those of Sp1 (189906) and BTEB1, respectively. Both BTEB2 and Sp1 have a short basic region preceding the zinc finger motifs that may play an auxiliary role in DNA binding. The N-terminal region of BTEB2 is proline rich. Recombinant BTEB2 protein and Sp1 showed very similar DNA-binding specificity in vitro. When expressed in mammalian cells, BTEB2 activated the transcription of a reporter gene fused to a GC box-containing promoter. Sogawa et al. (1993) also identified the rat BTEB2 homolog. Northern blot analysis of rat tissues revealed that BTEB2 is expressed only in the testis and placenta.
Suske et al. (2005) stated that the human KLF5 gene maps to chromosome 13q21.33, and the mouse Klf5 gene to chromosome 14E2.1.
KLF5 is a transcription factor for Smemb/nonmuscle myosin heavy chain B, which is a molecular marker of phenotypically modulated smooth muscle cells. Normally, KLF5 is abundantly expressed in developing blood vessels, but is downregulated in adult vessels. However, its expression is strongly upregulated in activated smooth muscle cells and fibroblasts (myofibroblasts) within vascular lesions. Shindo et al. (2002) generated Klf5 knockout mice. Homozygous mutants died before embryonic day 8.5. Klf5 +/- mice showed diminished levels of arterial wall thickening, angiogenesis, cardiac hypertrophy, and interstitial fibrosis in response to external stress. Shindo et al. (2002) demonstrated angiotensin II (106150)-induced expression of Klf5, which in turn activated platelet-derived growth factor-A (PDGFA; 173430) and transforming growth factor-beta (TGFB; 190180) expression. Shindo et al. (2002) also determined that Klf5 interacted with the retinoic-acid receptor (RAR; 180240), that synthetic Rar ligands modulated Klf5 transcriptional activity, and that in vivo administration of Rar ligands affected stress responses in the cardiovascular system in a Klf5-dependent manner. Shindo et al. (2002) concluded that Klf5 seems to be a key element in linking external stress and cardiovascular remodeling. KLF5 is also abundantly expressed in the gastrointestinal tract. In heterozygous mutant mice, Shindo et al. (2002) observed misshapen villi and reductions in the number of mesenchymal cells and the amount of extracellular matrix in the gastrointestinal tracts. Notably, the gastrointestinal phenotypes of Klf5 +/- mice were very similar to those of Pdgfa -/- mice, confirming that KLF5 and PDGFA occur in the same signaling pathway. Shindo et al. (2002) demonstrated that Pdgfa expression was significantly diminished in the gastrointestinal tract of Klf5 +/- mice at both the mRNA and protein levels.
Oishi et al. (2005) observed that Klf5-null mice were markedly deficient in white adipose tissue development and that Klf5 expression was induced at an early stage of differentiation in 3T3-L1 preadipocytes. Constitutive overexpression of dominant-negative Klf5 inhibited adipocyte differentiation, whereas overexpression of wildtype Klf5 induced differentiation even without hormonal stimulation. Adipocyte differentiation was much attenuated in embryonic fibroblasts obtained from Klf5 +/- mice. Oishi et al. (2005) concluded that KLF5 is a key regulator of adipocyte differentiation.
Oishi et al. (2008) generated Klf5 +/- mice and observed that they were resistant to high fat-induced obesity, hypercholesterolemia, and glucose intolerance, despite consuming more food than wildtype mice; the mutant mice also had an increased level of systemic energy expenditure compared to wildtype. Expression of genes involved in lipid oxidation and energy uncoupling, including Cpt1b (601987), Ucp2 (601693), and Ucp3 (602044), was upregulated. Under basal conditions, Klf5 modified with small ubiquitin-related modifier (SUMO) proteins (see 601912) was associated with transcriptionally repressive regulatory complexes containing unliganded Ppard (600409) and corepressors and thus inhibited Cpt1b, Ucp2, and Ucp3 expression. Upon agonist stimulation of Ppard, Klf5 was desumoylated and became associated with transcriptional activation complexes containing both the liganded Ppard and Crebbp (600140), which increased the expression of Cpt1b, Ucp2, and Ucp3. Oishi et al. (2008) concluded that sumoylation appears to be a molecular switch affecting function of KLF5 and the transcriptional regulatory programs governing lipid metabolism.
Oishi, Y., Manabe, I., Tobe, K., Ohsugi, M., Kubota, T., Fujiu, K., Maemura, K., Kubota, N., Kadowaki, T., Nagai, R. SUMOylation of Kruppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-delta. Nature Med. 14: 656-666, 2008. [PubMed: 18500350] [Full Text: https://doi.org/10.1038/nm1756]
Oishi, Y., Manabe, I., Tobe, K., Tsushima, K., Shindo, T., Fujiu, K., Nishimura, G., Maemura, K., Yamauchi, T., Kubota, N., Suzuki, R., Kitamura, T., Akira, S., Kadowaki, T., Nagai, R. Kruppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation. Cell Metab. 1: 27-39, 2005. [PubMed: 16054042] [Full Text: https://doi.org/10.1016/j.cmet.2004.11.005]
Shindo, T., Manabe, I., Fukushima, Y., Tobe, K., Aizawa, K., Miyamoto, S., Kawai-Kowase, K., Moriyama, N., Imai, Y., Kawakami, H., Nishimatsu, H., Ishikawa, T., and 10 others. Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling. Nature Med. 8: 856-863, 2002. [PubMed: 12101409] [Full Text: https://doi.org/10.1038/nm738]
Sogawa, K., Imataka, H., Yamasaki, Y., Kusume, H., Abe, H., Fujii-Kuriyama, Y. cDNA cloning and transcriptional properties of a novel GC box-binding protein, BTEB2. Nucleic Acids Res. 21: 1527-1532, 1993. [PubMed: 8479902] [Full Text: https://doi.org/10.1093/nar/21.7.1527]
Suske, G., Bruford, E., Philipsen, S. Mammalian SP/KLF transcription factors: bring in the family. Genomics 85: 551-556, 2005. [PubMed: 15820306] [Full Text: https://doi.org/10.1016/j.ygeno.2005.01.005]