SP and KLF Transcription Factors in Digestive Physiology and Diseases

Abstract

Specificity proteins (SPs) and Krüppel-like factors (KLFs) belong to the family of transcription factors that contain conserved zinc finger domains involved in binding to target DNA sequences. Many of these proteins are expressed in different tissues and have distinct tissue-specific activities and functions. Studies have shown that SPs and KLFs regulate not only physiological processes such as growth, development, differentiation, proliferation, and embryogenesis, but pathogenesis of many diseases, including cancer and inflammatory disorders. Consistently, these proteins have been shown to regulate normal functions and pathobiology in the digestive system. We review recent findings on the tissue- and organ-specific functions of SPs and KLFs in the digestive system including the oral cavity, esophagus, stomach, small and large intestines, pancreas, and liver. We provide a list of agents under development to target these proteins.

Keywords: Apoptosis; Cancer; Cell Cycle; Development; Differentiation; Digestive System; Krüppel-Like Factor; Proliferation; Specificity Protein; Stem Cells.

Figure 1. Structure of Human SP and KLF Proteins

The A, B, C, and D define the modules of SP1, TAD – transactivation, AD – activation, and RD – repression domain (reviewed in^-). The accession numbers of proteins used for this figure are listed per UniProtKB database as follows: SP1 (P08047), SP2 (Q02086), SP3 (Q02447), SP4 (Q02446), SP5 (Q6BEB4), SP6 (Q3SY56), SP7 (Q87DD2), SP8 (Q8IXZ3), SP9 (P0CG40), KLF1 (Q13351), KLF2 (Q9Y5W3), KLF3 (P57682), KLF4 (Q43474), KLF5 (Q13887), KLF6 (Q99612), KLF7 (O75840), KLF8 (O95600), KLF9 (Q13886), KLF10 (Q13118), KLF11 (O14901), KLF12 (Q9Y4X4), KLF13 (Q9Y2Y9), KLF14 (Q8TD49), KLF15 (Q9UIH9), KLF16 (Q9BXK1), and KLF17 (Q5JT82).

Figure 2. Post-translational Modifications and Co-factors That Interact With SP and KLF Proteins

SP/KLF protein is illustrated as a bar with the three zinc fingers identified near the carboxyl terminus. The various post-translational modifications are described above the protein and the various co-activators or co-repressors that interact with the protein below.

Figure 3. Expression Patterns of SP and KLF Proteins Under Physiologic Conditions in the Digestive System

The diagram illustrates the various organs or tissues in the digestive system, including the oral mucosa, esophagus, stomach, small intestine, colon, liver, and pancreas. Various members of SP and KLF proteins found in the given tissues or cells types are included in the figure.