Functional role of KLF10 in multiple disease processes

Abstract

Since the discovery by this laboratory of the zinc finger transcription factor, KLF10, a member of the Krüppel-like family of transcription factors, there have been multiple publications regarding its functions and its immediate family members, in numerous cell types. KLF10 has been shown to be rapidly induced by TGFbeta1, 2, 3, E(2), epidermal growth factor, and bone morphogenetic protein-2. TGFbeta inducible early gene-1 activates the TGFbeta-Smad signaling pathway via repression of Smad 7 expression and activation of Smad 2 expression and activity. Overall, KLF10 has been implicated in cell differentiation, as a target gene for a variety of signaling pathways, and in serving as a potential marker for human diseases such as breast cancer, cardiac hypertrophy, and osteoporosis. Like other KLF members, KLF10 is expressed in specific cell types in numerous tissues and is known to be involved in repressing cell proliferation and inflammation as well as inducing apoptosis similar to that of TGFbeta. KLF10 binds to Sp-1-GC rich DNA sequences and can activate or repress the transcription of a number of genes. Overall, KLF10 has been shown to play a major role in the TGFbeta inhibition of cell proliferation and inflammation and induction of apoptosis, and its overexpression in human osteoblasts and pancreatic carcinoma cells mimics the actions of TGFbeta.

Fig. 1

Model of the chromosomal locale and the genomic and protein structure of KLF10 (TIEG1). A. Genomic structure showing promoter, exons, and introns of KLF10. B. Protein structure of KLF10 showing various protein and DNA binding domains.

Fig. 2

This figure outlines the role of KLF10 protein as a target and as a regulator of the TGFβ-Smad 2,3 signaling pathway. TGFβ binds to its membrane receptors (R₂ R₁) to activate the Smad signaling pathway. KLF10 (TIEG) is one of the rapid, early response genes whose expression is activated. KLF10 mRNA is rapidly translated into the KLF10 protein, which as a gene transcription repressor inhibits Smad 7 gene expression and, as a gene activator, induces Smad 2 gene expression. The ultimate outcome is a continued activation of the TGFβ-Smad signaling pathway, that is, an extension of the signaling period. The KLF10 mRNA and protein are rapidly turned over, thus the signaling is fine tuned to the KLF10 levels and activity. The steroid, estrogen (E), also induces the expression of KLF10 gene transcription, which is one mechanism of the well documented crosstalk between TGFβ and estrogen signaling.

Fig. 3

Model depicting the KLF10 co-activation and compression of known target gene expression in bone forming osteoblast (OB) cells. The result of this gene regulation is the induction of osteoblast and osteoclast differentiation and encouragement of bone formation and remodeling.

Fig. 4

Reported defects/diseases of the KLF10 KO mouse. This table summarizes the cell and organ defects, which occur in KLF10 KO mice. Also listed are some of the genes whose expression are significantly altered in these cells/ organs. See text for referenced resources.

Fig. 5

Models depicting (A) normal/wild-type, and (B) KLF10 knockout mouse processes of osteoblast (OB) support of osteoclast (OCL) differentiation. In the wild-type mouse (A), the OBs are shown to produce high levels of RANKL and M-CSF required for OCL differentiation, as well as low levels of OPG, the inhibitor of OCL differentiation. The result is enhanced OCL differentiation, high bone turnover, and an increase in bone formation. In (B) the KLF10 ablated OB cells produce low levels of RANKL, high levels of OPG, which retards OCL differentiation. The result is a reduction in bone turnover and a loss of bone (osteopenia).

Fig. 6

Graph depicting the expression levels of KLF10 and its target genes (Smad 2, Bard 1, Smad 7) in human breast cancers at various stages. (Reproduced with permission from Reinholz et al. Breast Cancer Res. Treat., 86 (2004), 75–88).

Fig. 7

List of abnormal tissue structure and function which correlates with altered TIEG expression. (References to these relationships are also listed.)