Abstract
A number of KLF family members are known to play important roles in the regulation of proliferation, differentiation, and development of the gastrointestinal tract. Of these, KLF4 (previously known as GKLF or EZF) and KLF5 (previously known as IKLF or BTEB2) have been the most extensively studied. In this chapter, we review the expression patterns and established functions for KLF family members in the gastrointestinal tract and offer insight into possible future areas of investigation of the KLFs in gastrointestinal differentiation and development.
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Keywords
- Esophageal Squamous Cell Carcinoma
- Familial Adenomatous Polyposis
- Enteroendocrine Cell
- Esophageal Epithelium
- Physiol Gastrointest Liver
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References
Bateman, N. W., Tan, D., Pestell, R. G., Black, J. D., and Black, A. R. (2004). Intestinal tumor progression is associated with altered function of KLF5. J Biol Chem 279, 12093–12101.
Benzeno, S., Narla, G., Allina, J., Cheng, G. Z., Reeves, H. L., Banck, M. S., Odin, J. A., Diehl, J. A., Germain, D., and Friedman, S. L. (2004). Cyclin-dependent kinase inhibition by the KLF6 tumor suppressor protein through interaction with cyclin D1. Cancer Res 64, 3885–3891.
Chanchevalap, S., Nandan, M. O., Merlin, D., and Yang, V. W. (2004). All-trans retinoic acid inhibits proliferation of intestinal epithelial cells by inhibiting expression of the gene encoding Kruppel-like factor 5. FEBS Lett 578, 99–105.
Chen, X., Johns, D. C., Geiman, D. E., Marban, E., Dang, D. T., Hamlin, G., Sun, R., and Yang, V. W. (2001). Kruppel-like factor 4 (gut-enriched Kruppel-like factor) inhibits cell proliferation by blocking G1/S progression of the cell cycle. J Biol Chem 276, 30423–30428.
Chen, Y. J., Wu, C. Y., Chang, C. C., Ma, C. J., Li, M. C., and Chen, C. M. (2008). Nuclear Kruppel-like factor 4 expression is associated with human skin squamous cell carcinoma progression and metastasis. Cancer Biol Ther 7, 777–782.
Cho, Y. G., Choi, B. J., Kim, C. J., Song, J. W., Kim, S. Y., Nam, S. W., Lee, S. H., Yoo, N. J., Lee, J. Y., and Park, W. S. (2006a). Genetic alterations of the KLF6 gene in colorectal cancers. Apmis 114, 458–464.
Cho, Y. G., Choi, B. J., Song, J. W., Kim, S. Y., Nam, S. W., Lee, S. H., Yoo, N. J., Lee, J. Y., and Park, W. S. (2006b). Aberrant expression of kruppel-like factor 6 protein in colorectal cancers. World J Gastroenterol 12, 2250–2253.
Cho, Y. G., Kim, C. J., Park, C. H., Yang, Y. M., Kim, S. Y., Nam, S. W., Lee, S. H., Yoo, N. J., Lee, J. Y., and Park, W. S. (2005). Genetic alterations of the KLF6 gene in gastric cancer. Oncogene 24, 4588–4590.
Conkright, M. D., Wani, M. A., Anderson, K. P., and Lingrel, J. B. (1999). A gene encoding an intestinal-enriched member of the Kruppel-like factor family expressed in intestinal epithelial cells. Nucleic Acids Res 27, 1263–1270.
D'Souza, U. M., Lammers, C. H., Hwang, C. K., Yajima, S., and Mouradian, M. M. (2002). Developmental expression of the zinc finger transcription factor DRRF (dopamine receptor regulating factor). Mech Dev 110, 197–201.
Dang, D. T., Bachman, K. E., Mahatan, C. S., Dang, L. H., Giardiello, F. M., and Yang, V. W. (2000). Decreased expression of the gut-enriched Krüppel-like factor gene in intestinal adenomas of multiple intestinal neoplasia mice and in colonic adenomas of familial adenomatous polyposis patients. FEBS Lett 476, 203–207.
de Santa Barbara, P., van den Brink, G. R., and Roberts, D. J. (2003). Development and differentiation of the intestinal epithelium. Cell Mol Life Sci 60, 1322–1332.
Fitzgerald, R. C. (2006). Molecular basis of Barrett's oesophagus and oesophageal adenocar-cinoma. Gut 55, 1810–1820.
Garrett-Sinha, L. A., Eberspaecher, H., Seldin, M. F., and de Crombrugghe, B. (1996). A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells. Journal of Biological Chemistry 271, 31384–31390.
Ghaleb, A. M., McConnell, B. B., Nandan, M. O., Katz, J. P., Kaestner, K. H., and Yang, V. W. (2007). Haploinsufficiency of Kruppel-like factor 4 promotes adenomatous polyposis coli dependent intestinal tumorigenesis. Cancer Res 67, 7147–7154.
Ghaleb, A. M., Nandan, M. O., Chanchevalap, S., Dalton, W. B., Hisamuddin, I. M., and Yang, V. W. (2005). Kruppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation. Cell Res 15, 92–96.
Goldstein, B. G., Chao, H. H., Yang, Y., Yermolina, Y. A., Tobias, J. W., and Katz, J. P. (2007). Overexpression of Kruppel-like factor 5 in esophageal epithelia in vivo leads to increased proliferation in basal but not suprabasal cells. Am J Physiol Gastrointest Liver Physiol 292, G1784–1792.
Gordon, A. R., Outram, S. V., Keramatipour, M., Goddard, C. A., Colledge, W. H., Metcalfe, J. C., Hager-Theodorides, A. L., Crompton, T., and Kemp, P. R. (2008). Splenomegaly and modified erythropoiesis in KLF13–/– mice. J Biol Chem 283, 11897–11904.
Hinnebusch, B. F., Siddique, A., Henderson, J. W., Malo, M. S., Zhang, W., Athaide, C. P., Abedrapo, M. A., Chen, X., Yang, V. W., and Hodin, R. A. (2004). Enterocyte differentiation marker intestinal alkaline phosphatase is a target gene of the gut-enriched Krüppel-like factor. Am J Physiol Gastrointest Liver Physiol 286, G23–30.
Hogan, B. L. M., and Zaret, K. S. (2002). Mouse Development: Patterning, Morphogenesis, and Organogenesis (San Diego: Academic Press).
Hwang, C. K., D'Souza, U. M., Eisch, A. J., Yajima, S., Lammers, C. H., Yang, Y., Lee, S. H., Kim, Y. M., Nestler, E. J., and Mouradian, M. M. (2001). Dopamine receptor regulating factor, DRRF: a zinc finger transcription factor. Proc Natl Acad Sci U S A 98, 7558–7563.
Imataka, H., Sogawa, K., Yasumoto, K., Kikuchi, Y., Sasano, K., Kobayashi, A., Hayami, M., and Fujii-Kuriyama, Y. (1992). Two regulatory proteins that bind to the basic transcription element (BTE), a GC box sequence in the promoter region of the rat P-4501A1 gene. Embo J 11, 3663–3671.
Jenkins, T. D., Opitz, O. G., Okano, J., and Rustgi, A. K. (1998). Transactivation of the human keratin 4 and Epstein-Barr virus ED-L2 promoters by gut-enriched Kruppel-like factor. Journal of Biological Chemistry 273, 10747–10754.
Kaczynski, J. A., Conley, A. A., Fernandez Zapico, M., Delgado, S. M., Zhang, J. S., and Urrutia, R. (2002). Functional analysis of basic transcription element (BTE)-binding protein (BTEB) 3 and BTEB4, a novel Sp1-like protein, reveals a subfamily of transcriptional repressors for the BTE site of the cytochrome P4501A1 gene promoter. Biochem J 366, 873–882.
Kang, L., Lu, B., Xu, J., Hu, H., and Lai, M. (2008). Downregulation of Kruppel-like factor 9 in human colorectal cancer. Pathol Int 58, 334–338.
Karam, S. M. (1999). Lineage commitment and maturation of epithelial cells in the gut. Front Biosci 4, D286–298.
Katz, J. P., Perreault, N., Goldstein, B. G., Actman, L., McNally, S. R., Silberg, D. G., Furth, E. E., and Kaestner, K. H. (2005). Loss of KLF4 in mice causes altered proliferation and differentiation and precancerous changes in the adult stomach. Gastroenterology 128, 935–945.
Katz, J. P., Perreault, N., Goldstein, B. G., Lee, C. S., Labosky, P. A., Yang, V. W., and Kaestner, K. H. (2002). The zinc-finger transcription factor KLF4 is required for terminal differentiation of goblet cells in the colon. Development 129, 2619–2628.
Katz, J. P., and Wu, G. D. (2004). Abnormalities of gastrointestinal organogenesis, Vo l 2 (Philadelphia: Mosby).
Kaufman, M. M. (1995). The Atlas of Mouse Development, Revised edn (Academic Press: San Diego).
Koritschoner, N. P., Bocco, J. L., Panzetta-Dutari, G. M., Dumur, C. I., Flury, A., and Patrito, L. C. (1997). A novel human zinc finger protein that interacts with the core promoter element of a TATA box-less gene. J Biol Chem 272, 9573–9580.
Laub, F., Aldabe, R., Ramirez, F., and Friedman, S. (2001). Embryonic expression of Kruppel-like factor 6 in neural and non-neural tissues. Mech Dev 106, 167–170.
Lebenthal, E. (1989). Human gastrointestinal development (New York: Raven Press).
Luo, A., Kong, J., Hu, G., Liew, C. C., Xiong, M., Wang, X., Ji, J., Wang, T., Zhi, H., Wu, M., and Liu, Z. (2003). Discovery of Ca2+-relevant and differentiation-associated genes downregulated in esophageal squamous cell carcinoma using cDNA microarray. Oncogene.
Martin, K. M., Cooper, W. N., Metcalfe, J. C., and Kemp, P. R. (2000). Mouse BTEB3, a new member of the basic transcription element binding protein (BTEB) family, activates expression from GC-rich minimal promoter regions. Biochem J 345 Pt 3, 529–533.
Martin, K. M., Metcalfe, J. C., and Kemp, P. R. (2001). Expression of KLF9 and KLF13 in mouse development. Mech Dev 103, 149–151.
Matsumoto, N., Kubo, A., Liu, H., Akita, K., Laub, F., Ramirez, F., Keller, G., and Friedman, S. L. (2006). Developmental regulation of yolk sac hematopoiesis by Kruppel-like factor 6. Blood 107, 1357–1365.
McConnell, B. B., Ghaleb, A. M., Nandan, M. O., and Yang, V. W. (2007). The diverse functions of Kruppel-like factors 4 and 5 in epithelial biology and pathobiology. Bioessays 29, 549–557.
Moore, K. L., and Persaud, T. V. N. (1998). The developing human: clinically oriented embryology, 6th edn (Philadelphia: Saunders).
Morita, M., Kobayashi, A., Yamashita, T., Shimanuki, T., Nakajima, O., Takahashi, S., Ikegami, S., Inokuchi, K., Yamashita, K., Yamamoto, M., and Fujii-Kuriyama, Y. (2003). Functional analysis of basic transcription element binding protein by gene targeting technology. Mol Cell Biol 23, 2489–2500.
Nandan, M. O., McConnell, B. B., Ghaleb, A. M., Bialkowska, A. B., Sheng, H., Shao, J., Babbin, B. A., Robine, S., and Yang, V. W. (2008). Kruppel-like factor 5 mediates cellular transformation during oncogenic KRAS-induced intestinal tumorigenesis. Gastroenterology 134, 120–130.
Narla, G., Heath, K. E., Reeves, H. L., Li, D., Giono, L. E., Kimmelman, A. C., Glucksman, M. J., Narla, J., Eng, F. J., Chan, A. M., et al. (2001). KLF6, a candidate tumor suppressor gene mutated in prostate cancer. Science 294, 2563–2566.
Ohnishi, S., Laub, F., Matsumoto, N., Asaka, M., Ramirez, F., Yoshida, T., and Terada, M. (2000). Developmental expression of the mouse gene coding for the Kruppel-like transcription factor KLF5. Dev Dyn 217, 421–429.
Okano, J., Opitz, O. G., Nakagawa, H., Jenkins, T. D., Friedman, S. L., and Rustgi, A. K. (2000). The Krüppel-like transcriptional factors Zf9 and GKLF coactivate the human keratin 4 promoter and physically interact. FEBS Lett 473, 95–100.
Pandya, A. Y., Talley, L. I., Frost, A. R., Fitzgerald, T. J., Trivedi, V., Chakravarthy, M., Chhieng, D. C., Grizzle, W. E., Engler, J. A., Krontiras, H., et al. (2004). Nuclear localization of KLF4 is associated with an aggressive phenotype in early-stage breast cancer. Clin Cancer Res 10, 2709–2719.
Peng, D., Sheta, E. A., Powell, S. M., Moskaluk, C. A., Washington, K., Goldknopf, I. L., and El-Rifai, W. (2008). Alterations in Barrett's-related adenocarcinomas: a proteomic approach. Int J Cancer 122, 1303–1310.
Que, J., Choi, M., Ziel, J. W., Klingensmith, J., and Hogan, B. L. (2006). Morphogenesis of the trachea and esophagus: current players and new roles for noggin and Bmps. Differentiation 74, 422–437.
Reeves, H. L., Narla, G., Ogunbiyi, O., Haq, A. L., Katz, A., Benzeno, S., Hod, E., Harpaz, N., Goldberg, S., Tal-Kremer, S., Eng, F. J., Arthur, M. J., Martignetti, J. A., and Friedman, S. L. (2004). Krüppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer. Gastroenterology 126, 1090–1103.
Roberts, D. J. (2000). Molecular mechanisms of development of the gastrointestinal tract. Dev Dyn 219, 109–120.
Rowland, B. D., Bernards, R., and Peeper, D. S. (2005). The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene. Nat Cell Biol 7, 1074–1082.
Scohy, S., Gabant, P., Van Reeth, T., Hertveldt, V., Dreze, P. L., Van Vooren, P., Riviere, M., Szpirer, J., and Szpirer, C. (2000). Identification of KLF13 and KLF14 (SP6), novel members of the SP/XKLF transcription factor family. Genomics 70, 93–101.
Seery, J. P. (2002). Stem cells of the oesophageal epithelium. J Cell Sci 115, 1783–1789.
Segre, J. A., Bauer, C., and Fuchs, E. (1999). KLF4 is a transcription factor required for establishing the barrier function of the skin. Nat Genet 22, 356–360.
Shie, J. L., Chen, Z. Y., O'Brien, M. J., Pestell, R. G., Lee, M. E., and Tseng, C. C. (2000). Role of gut-enriched Kruppel-like factor in colonic cell growth and differentiation. Am J Physiol Gastrointest Liver Physiol 279, G806–814.
Shields, J. M., Christy, R. J., and Yang, V. W. (1996). Identification and characterization of a gene encoding a gut-enriched Krüppel-like factor expressed during growth arrest. Journal of Biological Chemistry 271, 20009–20017.
Shindo, T., Manabe, I., Fukushima, Y., Tobe, K., Aizawa, K., Miyamoto, S., Kawai-Kowase, K., Moriyama, N., Imai, Y., Kawakami, H., et al. (2002). Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling. Nat Med 8, 856–863.
Simmen, F. A., Xiao, R., Velarde, M. C., Nicholson, R. D., Bowman, M. T., Fujii-Kuriyama, Y., Oh, S. P., and Simmen, R. C. (2007). Dysregulation of intestinal crypt cell proliferation and villus cell migration in mice lacking Kruppel-like factor 9. Am J Physiol Gastrointest Liver Physiol 292, G1757–1769.
Simmen, R. C., Eason, R. R., McQuown, J. R., Linz, A. L., Kang, T. J., Chatman, L., Jr., Till, S. R., Fujii-Kuriyama, Y., Simmen, F. A., and Oh, S. P. (2004). Subfertility, uterine hypoplasia, and partial progesterone resistance in mice lacking the Kruppel-like factor 9/basic transcription element-binding protein-1 (Bteb1) gene. J Biol Chem 279, 29286–29294.
Sun, R., Chen, X., and Yang, V. W. (2001). Intestinal-enriched Kruppel-like factor (Kruppel-like factor 5) is a positive regulator of cellular proliferation. J Biol Chem 276, 6897–6900.
Ton-That, H., Kaestner, K. H., Shields, J. M., Mahatanankoon, C. S., and Yang, V. W. (1997). Expression of the gut-enriched Kruppel-like factor gene during development and intestinal tumorigenesis. FEBS Letters 419, 239–243.
Traber, P. G., and Silberg, D. G. (1996). Intestine-specific gene transcription. Annu Rev Physiol 58, 275–297.
Traber, P. G., and Wu, G. D. (1995). Intestinal Development and Differentiation (Philadelphia: Lippencott-Raven).
Wang, N., Liu, Z. H., Ding, F., Wang, X. Q., Zhou, C. N., and Wu, M. (2002). Down-regulation of gut-enriched Krüppel-like factor expression in esophageal cancer. World J Gastroenterol 8, 966–970.
Wei, D., Gong, W., Kanai, M., Schlunk, C., Wang, L., Yao, J. C., Wu, T. T., Huang, S., and Xie, K. (2005). Drastic down-regulation of Krüppel-like factor 4 expression is critical in human gastric cancer development and progression. Cancer Res 65, 2746–2754.
Wells, J. M., and Melton, D. A. (1999). Vertebrate endoderm development. Annu Rev Cell Dev Biol 15, 393–410.
Yamashita, K., Upadhyay, S., Osada, M., Hoque, M. O., Xiao, Y., Mori, M., Sato, F., Meltzer, S. J., and Sidransky, D. (2002). Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma. Cancer Cell 2, 485–495.
Yang, Q., Bermingham, N. A., Finegold, M. J., and Zoghbi, H. Y. (2001). Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294, 2155–2158.
Yang, Y., Goldstein, B. G., Chao, H. H., and Katz, J. P. (2005). KLF4 and KLF5 regulate proliferation, apoptosis and invasion in esophageal cancer cells. Cancer Biol Ther 4, 1216–1221.
Yang, Y., Goldstein, B. G., Nakagawa, H., and Katz, J. P. (2007). Kruppel-like factor 5 activates MEK/ERK signaling via EGFR in primary squamous epithelial cells. Faseb J 21, 543–550.
Yang, Y., Tetreault, M. P., Yermolina, Y. A., Goldstein, B. G., and Katz, J. P. (2008). Kruppel-like factor 5 controls keratinocyte migration via the integrin-linked kinase. J Biol Chem 283, 18812–18820.
Yoon, H. S., Chen, X., and Yang, V. W. (2003). Krüppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage. J Biol Chem 278, 2101–2105.
Yoon, H. S., Ghaleb, A. M., Nandan, M. O., Hisamuddin, I. M., Dalton, W. B., and Yang, V. W. (2005). Krüppel-like factor 4 prevents centrosome amplification following gamma-irradiation-induced DNA damage. Oncogene.
Zhao, W., Hisamuddin, I. M., Nandan, M. O., Babbin, B. A., Lamb, N. E., and Yang, V. W. (2004). Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer. Oncogene 23, 395–402.
Zhou, M., McPherson, L., Feng, D., Song, A., Dong, C., Lyu, S. C., Zhou, L., Shi, X., Ahn, Y. T., Wang, D., et al. (2007). Kruppel-like transcription factor 13 regulates T lymphocyte survival in vivo. J Immunol 178, 5496–5504.
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Tétreault, MP., Katz, J.P. (2009). Krüppel-like Factors in Gastrointestinal Tract Development and Differentiation. In: Nagai, R., Friedman, S.L., Kasuga, M. (eds) The Biology of Krüppel-like Factors. Springer, Tokyo. https://doi.org/10.1007/978-4-431-87775-2_8
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