The Krüppel-like factors in female reproductive system pathologies

Abstract

Female reproductive tract pathologies arise largely from dysregulation of estrogen and progesterone receptor signaling, leading to aberrant cell proliferation, survival, and differentiation. The signaling pathways orchestrated by these nuclear receptors are complex, require the participation of many nuclear proteins serving as key binding partners or targets, and involve a range of paracrine and autocrine regulatory circuits. The members of the Krüppel-like factor (KLF) family of transcription factors are ubiquitously expressed in reproductive tissues and have been increasingly implicated as critical co-regulators and integrators of steroid hormone actions. Herein, we explore the involvement of KLF family members in uterine pathology, describe their currently known molecular mechanisms, and discuss their potential as targets for therapeutic intervention.

Keywords: KLF; Notch; Wnt; endometrial pathologies; progesterone.

Figure 1

KLF members and their functional domains. (A) Schematic diagram of the highly variable amino-terminal (transactivation domain) and the highly conserved carboxy-terminal (DNA-binding domain) regions of KLF member proteins. (B) Sequence homology among human and mouse KLF9 and KLF13 proteins. Invariant (Red), conserved (blue) and variable (black) amino acid residues are depicted as single-letter codes. (C) KLFs are assigned to three sub-groups based on their phylogenetic relationships (Limame et al., 2014).

Figure 2

Signaling pathways and gene targets associated with dysregulated expression of KLF family members in the pathologic uterus (A) and ovary (B). Arrows in panel B (↑ and ↓) signify up- and down-regulated expression of each KLF with ovarian carcinoma.

Figure 3

Expression of select KLFs in young and aging mouse uteri. Transcript levels of various KLFs were quantified in 8- and 27-month old C57BL/6 mouse uteri by quantitative RT-PCR. Data (mean ± SEM) are expressed as fold-change and were obtained from n=7 individual mice per age group. Transcript levels were normalized to corresponding levels of 18S, and then to control (8-month old uteri) and were calibrated to a standard curve using pooled cDNA stocks. *, significant at P<0.05, by t-test; #, tending to significance with 0.05<P<0.10

Figure 4

Complex and redundant control by KLFs of PGR and ESR1 signaling in distinct uterine compartments. Promotion or inhibition of PGR and ESR1 activity may occur by direct or indirect mechanisms. Arrows originating from P/PGR (in epithelium) depict KLFs as integrators of P/PGR signaling. Bi-directional arrows between stroma and epithelium signify the dynamic communication between the two endometrial compartments.