The diverse functions of Krüppel-like factors 4 and 5 in epithelial biology and pathobiology

Abstract

The Krüppel-like factors (KLFs) comprise a family of evolutionarily conserved zinc finger transcription factors that regulate numerous biological processes including proliferation, differentiation, development and apoptosis. KLF4 and KLF5 are two closely related members of this family and are both highly expressed in epithelial tissues. In the intestinal epithelium, KLF4 is expressed in terminally differentiated epithelial cells at the villus borders of the mucosa and inhibits cell growth, while KLF5 is expressed in proliferating epithelial cells at the base of the intestinal crypts and promotes cell growth. KLF4 and KLF5 respond to a myriad of external stress stimuli and are likely involved in restoring cellular homeostasis following exposure to stressors. Confirming their importance in maintaining tissue integrity, KLF4 and KLF5 are both dysregulated in various types of cancer. Here we review the recent advances in defining the physiological and pathobiological roles of KLF4 and KLF5, focusing on their functions in the intestinal epithelium.

Figure 1

Localization of Klf4 and Klf5 in mouse small and large intestine. Immunostaining of Klf4 and Klf5 shows that Klf4 is present in the nuclei of terminally differentiated epithelial cells in the villi and upper crypts of the small and large intestine, respectively. In contrast, Klf5 exhibits nuclear expression in proliferating epithelial cells at the base of the crypts in both tissues.

Figure 2

Participation of KLF4 and KLF5 in cell cycle regulation. KLF4 is induced by DNA damage or serum starvation and has a growth inhibitory role by regulating expression of keycell cycle genes, including the cell cycle inhibitor, p21^Cip1/Kip1. In contrast, KLF5 plays a growth-promoting role in response to mitogenic signals through its activation of cyclin D, cyclin B, and the cyclin B kinase, Cdc2.

Figure 3

Models for the dual roles of KLF4 and KLF5 in tumor suppression and oncogenesis. A: KLF4 normally acts as a tumor suppressor through p21^Cip1/Kip1-dependent cell cycle arrest. However, in the presence of an oncogenic signal (such as Ras^v12), the p21^Cip1/Kip1 pathway is inactivated, and the anti-apoptotic activity of KLF4 provides a survival advantage, allowing for cellular transformation. B: The pro-proliferative activity of KLF5 contributes to transformation in response to oncogenic signals, such as H- or K-Ras. However, in certain contexts, KLF5 may also possess growth inhibitory activities in the presence of an oncogenic signal that allow it to act as a tumor suppressor, overriding its growth-promoting effects.