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.

Fig 1

A model by which KLF4 mediates the cell cycle checkpoint functions of p53 in response to DNA damage. The tumor suppressor p53 is activated in response to DNA damage, which in turn activates KLF4. KLF4 then exerts a multitude of effects on expression of downstream genes by activating (→) or inhibiting their expression (⊣). References in support of the specific pathways are as follows: p53 → KLF4 → p21 [16]; KLF4 ⊣ cyclin D/Cdk4 [19]; KLF4 ⊣ cyclin B/Cdc2 [18]; KLF4 ⊣ cyclin E/Cdk2 [21]; KLF4 ⊣ STK15 [20]; KLF4 → 14-3-3 σ; KLF4 ⊣ BUB1/MAD2 [20].

Fig. 2

KLF5 is central in mediating the transforming effect of oncogenic H-Ras. The sequence of events from oncogenic H-Ras to KLF5 and subsequent target gene expression is shown. MAPK is mitogen-activated protein kinase. See reference [28] for detail. The effect of KLF5 on cyclin B1/Cdc2 expression is unpublished.