Essential role of KLF5 transcription factor in cell proliferation and differentiation and its implications for human diseases

Abstract

KLF5 (Kruppel-like factor 5) is a basic transcription factor binding to GC boxes at a number of gene promoters and regulating their transcription. KLF5 is expressed during development and, in adults, with higher levels in proliferating epithelial cells. The expression and activity of KLF5 are regulated by multiple signaling pathways, including Ras/MAPK, PKC, and TGFbeta, and various posttranslational modifications, including phosphorylation, acetylation, ubiquitination, and sumoylation. Consistently, KLF5 mediates the signaling functions in cell proliferation, cell cycle, apoptosis, migration, differentiation, and stemness by regulating gene expression in response to environment stimuli. The expression of KLF5 is frequently abnormal in human cancers and in cardiovascular disease-associated vascular smooth muscle cells (VSMCs). Due to its significant functions in cell proliferation, survival, and differentiation, KLF5 could be a potential diagnostic biomarker and therapeutic target for cancer and cardiovascular diseases.

Fig. 1

The human KLF5 gene and protein structures. The human KLF5 genome contains four exons (exon 1, 585 bp; intron 1, 2,272 bp; exon 2, 874 bp; intron 2, 1,089 bp; exon 3, 60 bp; intron 3, 11,824 bp; and exon 4, 1,831 bp). The KLF5 protein contains three zinc-finger (ZF) domains, one major transactivation domain (TAD) with a PY motif (PPSY328), and a nucleus export signal (NES). The KLF5 protein undergoes different types of posttranslational modifications, including phosphorylation (P at S153), acetylation (Ac at K369), ubiquitination (Ub), and sumoylation (Su at K162 and K209)

Fig. 2

The regulatory signaling pathways for KLF5. KLF5 is regulated by multiple signaling pathways at the transcriptional and posttranslational levels. LPA Lysophosphatidic acid, LPS lipopolysaccharide, PMA phorbol 12-myristate 13-acetate, S1P sphingosine 1-phosphate, BIP bisindolyimalimide