Spatial and temporal expression patterns of KLF5 suggest a role in proliferation in many systems. Expression levels of KLF5 are high in actively dividing cell types such as embryonic stem cells (ESCs) or proliferating cells of the intestinal epithelium, and expression decreases on differentiation to terminally mature cells [12, 13]. Accordingly, serum or cytokine stimulation of fibroblasts and smooth muscle cells induces proliferation with a concordant increase in KLF5 expression [5, 14]. KLF5 expression is induced in rodent models of biological stress caused by physical injury, irradiation or bacterial pathogens, suggesting a proliferative and/or migratory role in the body's inflammatory and immune response systems [7, 15-19].
Ectopic expression of KLF5 in a variety of cell types provides supporting evidence for a role in positive regulation of cellular proliferation. KLF5 increases growth rates of intestinal and esophageal epithelial cells, keratinocytes, VSMCs, and NIH-3T3 fibroblasts [20-24]. RNA interference (RNAi) knock-down of Klf5 shows the expected opposite effect with reduced cellular proliferation of keratinocytes and VSMCs [14, 24, 25]. In vivo studies support a growth-promoting role for KLF5 in the intestine, with heterozygous knock-out mice displaying shorter intestinal crypts and villi and decreased thickening of arterial walls, whilst conditional deletion of KLF5 in intestinal epithelium abolishes epithelial cell proliferation and results in neonatal lethality . Ablation or transgenic expression of KLF5 in mouse models of dextran sodium sulfate-induced colitis leads to increased or reduced disease severity respectively due to the essential role for KLF5 in epithelial cell proliferation and migration in the colon [27, 28]. KLF5 also contributes to vasculogenesis and angiogenesis via up-regulation of genes which increase VSMC proliferation and migration, and prevent differentiation, such as VEGFA, MYH10, TAGLN, SERPINE1, and EGR1 [7, 26, 29-31]. Accordingly, rat models of cardiovascular injury have shown that expression of KLF5 leads to enhanced neointima formation due to increased proliferation and migration of VSMCs [23, 25, 32]. In pulmonary arterial hypertension, a disease characterized by enhanced proliferation and suppressed apoptosis of pulmonary VSMCs, ablation of KLF5 in human explant cell models increased expression of the proliferative markers Ki67 and PCNA, and in rodent models delivery of a KLF5 siRNA to pulmonary VSMCs reduced disease severity . In embryonic stem cells, KLF5 plays an essential role in self-renewal via direct regulation of the pluripotency genes OCT4, Nanog, TCL1, and BMP4 (reviewed by Bourillot and Savatier ). Ablation of KLF5 through gene targeting induces G1 cell cycle arrest accompanied by induction of spontaneous differentiation, and accordingly homozygous KLF5 null mice result in early embryonic lethality (before e8.5).