Krüppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation

Abstract

Krüppel-like factors (KLFs) are evolutionarily conserved zinc finger-containing transcription factors with diverse regulatory functions in cell growth, proliferation, differentiation, and embryogenesis. KLF4 and KLF5 are two closely related members of the KLF family that have a similar tissue distribution in embryos and adults. However, the two KLFs often exhibit opposite effects on regulation of gene transcription, despite binding to similar, if not identical, cis-acting DNA sequences. In addition, KLF4 and 5 exert contrasting effects on cell proliferation in many instances; while KLF4 is an inhibitor of cell growth, KLF5 stimulates proliferation. Here we review the biological properties and biochemical mechanisms of action of the two KLFs in the context of growth regulation.

The E3 Ubiquitin Ligase SMAD Ubiquitination Regulatory Factor 2 Negatively Regulates Krüppel-like Factor 5 Protein

“…The intestinal epithelium is a highly polarized system containing terminally differentiated epithelial cells at villi and proliferating and progenitor cells in crypts (14). As the KLF5 protein is highly abundant in the crypt cell population with a diminishing gradient as cells migrate toward the villus (27,30,31), SMURF2 may form an opposite gradient along the crypt/ villus axis or contribute to establishing the polarity of the intestinal tract.…”

KLF4, p21 and context-dependent opposing forces in cancer

“…Although at least some of the functions of KLF4 and KLF6 seem to be similar, KLF5 has been proposed to have complementary functions to those of KLF4 (REF. 14), in that they have opposing effects on the expression of their shared target genes [64][65][66] . It is not entirely clear whether the settings in which KLF4 functions as an oncogene are similar to those in which KLF5 functions as a tumour suppressor, or vice versa.…”

“…For example, KLF6 has been described as a tumour suppressor in multiple cancer types, including prostate carcinomas 13 . Remarkably, KLF4 and KLF5 have been described as both tumour suppressors and oncogenes 14 .…”

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

“…In general, KLF4 is usually present in well-differentiated, non-proliferating cells, where it serves the role of growth suppressor and is activated strongly in fibroblasts arrested by serum withdrawal (reviewed in Ghaleb et al, 2005). Profiling experiments have shown that KLF4 activates genes that inhibit proliferation, and represses genes that promote it Whitney et al, 2006;Swamynathan et al, 2008).…”