The double life of KLF5: Opposing roles in regulation of gene‐expression, cellular function, and transformation

The mechanisms by which cells control their growth and behavioral identities are complex and require adaptability to environmental changes. Transcription factors act as master controllers of many of these pivotal points through their ability to influence the expression of many thousands of downstream genes, and increasingly research is showing that transcription factor regulation of target genes can change in response to environmental stimuli and cell type such that their function is not prescribed but rather context‐dependent. Krüppel like factor 5 (KLF5) is an example of such a transcription factor, where evidence of disparate effects on cell growth and differentiation in normal and transformed tissue are clear. Here we present and discuss the literature covering the differential roles of KLF5 in particular tissues and cancer states, and the mechanisms by which these differences are effected through the regulation of KLF5 protein function in response to different cellular states and the direct effect on target gene expression. © 2013 IUBMB Life, 65(12):999–1011, 2013

[1]  P. Guo,et al.  Different Expression Patterns and Functions of Acetylated and Unacetylated Klf5 in the Proliferation and Differentiation of Prostatic Epithelial Cells , 2013, PloS one.

[2]  I. Lewis,et al.  Methylation of KLF5 contributes to reduced expression in acute myeloid leukaemia and is associated with poor overall survival , 2013, British journal of haematology.

[3]  J. Whitsett,et al.  Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated β1/β2-integrin trafficking , 2013, Nature Communications.

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[5]  Yizeng Yang,et al.  p53 mutation alters the effect of the esophageal tumor suppressor KLF5 on keratinocyte proliferation , 2012, Cell cycle.

[6]  Zhongmei Zhou,et al.  YAP promotes breast cell proliferation and survival partially through stabilizing the KLF5 transcription factor. , 2012, The American journal of pathology.

[7]  Marie-Pier Tétreault,et al.  Krüppel-Like Factor 5 Protects against Murine Colitis and Activates JAK-STAT Signaling In Vivo , 2012, PloS one.

[8]  Bin Zheng,et al.  KLF5 and hhLIM cooperatively promote proliferation of vascular smooth muscle cells , 2012, Molecular and Cellular Biochemistry.

[9]  Dar-Ren Chen,et al.  Association of Expression of Kruppel-Like Factor 4 and Kruppel-Like Factor 5 with the Clinical Manifestations of Breast Cancer , 2012, Pathology & Oncology Research.

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[12]  V. Yang,et al.  Krüppel-like factor 5 is important for maintenance of crypt architecture and barrier function in mouse intestine. , 2011, Gastroenterology.

[13]  Mei Han,et al.  HDAC2 phosphorylation-dependent Klf5 deacetylation and RARα acetylation induced by RAR agonist switch the transcription regulatory programs of p21 in VSMCs , 2011, Cell Research.

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[15]  V. Yang,et al.  The E3 Ubiquitin Ligase SMAD Ubiquitination Regulatory Factor 2 Negatively Regulates Krüppel-like Factor 5 Protein* , 2011, The Journal of Biological Chemistry.

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[17]  J. Whitsett,et al.  Kruppel-like factor 5 is required for formation and differentiation of the bladder urothelium. , 2011, Developmental biology.

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[32]  Shuangxi Li,et al.  The Fbw7/Human CDC4 Tumor Suppressor Targets Proproliferative Factor KLF5 for Ubiquitination and Degradation through Multiple Phosphodegron Motifs* , 2010, The Journal of Biological Chemistry.

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[34]  Mei Han,et al.  Angiotensin II stimulates KLF5 phosphorylation and its interaction with c-Jun leading to suppression of p21 expression in vascular smooth muscle cells. , 2009, Journal of biochemistry.

[35]  Zhongmei Zhou,et al.  Krüppel-like factor 5 promotes breast cell proliferation partially through upregulating the transcription of fibroblast growth factor binding protein 1 , 2009, Oncogene.

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[41]  K. Zhao,et al.  Acetylation of KLF5 Alters the Assembly of p15 Transcription Factors in Transforming Growth Factor-β-mediated Induction in Epithelial Cells* , 2009, The Journal of Biological Chemistry.

[42]  Zhongmei Zhou,et al.  KLF5 Promotes Breast Cell Survival Partially through Fibroblast Growth Factor-binding Protein 1-pERK-mediated Dual Specificity MKP-1 Protein Phosphorylation and Stabilization* , 2009, The Journal of Biological Chemistry.

[43]  Mei Han,et al.  Synthetic retinoid Am80 inhibits interaction of KLF5 with RARα through inducing KLF5 dephosphorylation mediated by the PI3K/Akt signaling in vascular smooth muscle cells , 2009, FEBS letters.

[44]  Toru Suzuki,et al.  Krüppel-like Factor 5 Shows Proliferation-specific Roles in Vascular Remodeling, Direct Stimulation of Cell Growth, and Inhibition of Apoptosis* , 2009, Journal of Biological Chemistry.

[45]  Mei Han,et al.  Synthetic retinoid Am80 inhibits interaction of KLF5 with RAR¦Á through inducing KLF5 dephosphorylation mediated by the PI3K/Akt signaling in vascular smooth muscle cells , 2009 .

[46]  Xiaohui Zhang,et al.  Pro-proliferative Factor KLF5 Becomes Anti-proliferative in Epithelial Homeostasis upon Signaling-mediated Modification* , 2009, Journal of Biological Chemistry.

[47]  V. Yang,et al.  SUMOylation Regulates Nuclear Localization of Krüppel-like Factor 5* , 2008, Journal of Biological Chemistry.

[48]  Kozo Nakamura,et al.  Krüppel-like Factor 5 Causes Cartilage Degradation through Transactivation of Matrix Metalloproteinase 9* , 2008, Journal of Biological Chemistry.

[49]  J. Whitsett,et al.  Kruppel-like factor 5 is required for perinatal lung morphogenesis and function , 2008, Development.

[50]  Marie-Pier Tétreault,et al.  Krüppel-like Factor 5 Controls Keratinocyte Migration via the Integrin-linked Kinase* , 2008, Journal of Biological Chemistry.

[51]  Mitsuru Ohsugi,et al.  SUMOylation of Krüppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-δ , 2008, Nature Medicine.

[52]  Toru Suzuki,et al.  Acyclic retinoid inhibits functional interaction of transcription factors Krüppel‐like factor 5 and retinoic acid receptor‐alpha , 2008, FEBS letters.

[53]  V. Yang,et al.  Krüppel-like factor 5 mediates transmissible murine colonic hyperplasia caused by Citrobacter rodentium infection. , 2008, Gastroenterology.

[54]  O. Shirakawa,et al.  Expression of Kruppel-like factor 5 gene in human brain and association of the gene with the susceptibility to schizophrenia , 2008, Schizophrenia Research.

[55]  Sheng Zhong,et al.  A core Klf circuitry regulates self-renewal of embryonic stem cells , 2008, Nature Cell Biology.

[56]  K. Soo,et al.  Kruppel-like factor 5 modulates p53-independent apoptosis through Pim1 survival kinase in cancer cells , 2008, Oncogene.

[57]  M. Horikoshi,et al.  Promoter Region-Specific Histone Incorporation by the Novel Histone Chaperone ANP32B and DNA-Binding Factor KLF5 , 2007, Molecular and Cellular Biology.

[58]  V. Yang,et al.  The diverse functions of Krüppel‐like factors 4 and 5 in epithelial biology and pathobiology , 2007, BioEssays : news and reviews in molecular, cellular and developmental biology.

[59]  J. Tobias,et al.  Overexpression of Kruppel-like factor 5 in esophageal epithelia in vivo leads to increased proliferation in basal but not suprabasal cells. , 2007, American journal of physiology. Gastrointestinal and liver physiology.

[60]  M. Horikoshi,et al.  Functional Interaction between the Transcription Factor Krüppel-like Factor 5 and Poly(ADP-ribose) Polymerase-1 in Cardiovascular Apoptosis* , 2007, Journal of Biological Chemistry.

[61]  Zhongmei Zhou,et al.  Proteasomal degradation of the KLF5 transcription factor through a ubiquitin‐independent pathway , 2007, FEBS letters.

[62]  V. Yang,et al.  Protein Inhibitor of Activated STAT1 Interacts with and Up-regulates Activities of the Pro-proliferative Transcription Factor Krüppel-like Factor 5* , 2007, Journal of Biological Chemistry.

[63]  H. Nakagawa,et al.  Krüppel‐like factor 5 activates MEK/ERK signaling via EGFR in primary squamous epithelial cells , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[64]  I. Tomlinson,et al.  Colorectal cancer and genetic alterations in the Wnt pathway , 2006, Oncogene.

[65]  V. Jaks,et al.  Epidermal and craniofacial defects in mice overexpressing Klf5 in the basal layer of the epidermis , 2006, Journal of Cell Science.

[66]  R. Bafford,et al.  Angiotensin II and tumor necrosis factor-alpha upregulate survivin and Kruppel-like factor 5 in smooth muscle cells: Potential relevance to vein graft hyperplasia. , 2006, Surgery.

[67]  H. Frierson,et al.  Increased cytoplasmic localization of KLF5 in prostate cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[68]  Lily Yang,et al.  KLF5 Interacts with p53 in Regulating Survivin Expression in Acute Lymphoblastic Leukemia* , 2006, Journal of Biological Chemistry.

[69]  G. Heinze,et al.  Expression of KLF5 is a Prognostic Factor for Disease-Free Survival and Overall Survival in Patients with Breast Cancer , 2006, Clinical Cancer Research.

[70]  J. Simons,et al.  KLF5 promotes cell proliferation and tumorigenesis through gene regulationin the TSU‐Pr1 human bladder cancer cell line , 2006, International journal of cancer.

[71]  V. Yang,et al.  Krüppel-like factor 5 is an important mediator for lipopolysaccharide-induced proinflammatory response in intestinal epithelial cells , 2006, Nucleic acids research.

[72]  J. Simons,et al.  Human Kruppel-like Factor 5 Is a Target of the E3 Ubiquitin Ligase WWP1 for Proteolysis in Epithelial Cells* , 2005, Journal of Biological Chemistry.

[73]  K. Fujiu,et al.  Synthetic Retinoid Am80 Suppresses Smooth Muscle Phenotypic Modulation and In-Stent Neointima Formation by Inhibiting KLF5 , 2005, Circulation research.

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[76]  M. Horikoshi,et al.  The Deacetylase HDAC1 Negatively Regulates the Cardiovascular Transcription Factor Krüppel-like Factor 5 through Direct Interaction* , 2005, Journal of Biological Chemistry.

[77]  V. Yang,et al.  All‐trans retinoic acid inhibits proliferation of intestinal epithelial cells by inhibiting expression of the gene encoding Krüppel‐like factor 5 , 2004, FEBS letters.

[78]  V. Yang,et al.  Krüppel-like factor 5 mediates the transforming activity of oncogenic H-Ras , 2004, Oncogene.

[79]  Zhongmei Zhou,et al.  Regulation of KLF5 involves the Sp1 transcription factor in human epithelial cells. , 2004, Gene.

[80]  D. Tan,et al.  Intestinal Tumor Progression Is Associated with Altered Function of KLF5* , 2004, Journal of Biological Chemistry.

[81]  F. Stewart,et al.  Microarray analysis to identify molecular mechanisms of radiation-induced microvascular damage in normal tissues. , 2004, International journal of radiation oncology, biology, physics.

[82]  Toru Suzuki,et al.  Regulation of Platelet-derived Growth Factor-A Chain by Krüppel-like Factor 5* , 2004, Journal of Biological Chemistry.

[83]  A. Kimura,et al.  Positive and Negative Regulation of the Cardiovascular Transcription Factor KLF5 by p300 and the Oncogenic Regulator SET through Interaction and Acetylation on the DNA-Binding Domain , 2003, Molecular and Cellular Biology.

[84]  R. Doty,et al.  Regulation of T-cell receptor D beta 1 promoter by KLF5 through reiterated GC-rich motifs. , 2003, Blood.

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[90]  I. Sur,et al.  Human Krüppel-like factor5/KLF5: synergy with NF-kappaB/Rel factors and expression in human skin and hair follicles. , 2002, European journal of cell biology.

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[95]  Christopher P. Regan,et al.  Positive- and Negative-acting Krüppel-like Transcription Factors Bind a Transforming Growth Factor β Control Element Required for Expression of the Smooth Muscle Cell Differentiation Marker SM22α in Vivo * , 2000, The Journal of Biological Chemistry.

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[107]  Zhongmei Zhou,et al.  TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes breast cell proliferation and tumorigenesis. , 2012, Carcinogenesis.

[108]  Mei Han,et al.  Krüppel-like factor (KLF) 5 mediates cyclin D1 expression and cell proliferation via interaction with c-Jun in Ang II-induced VSMCs , 2010, Acta Pharmacologica Sinica.

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[110]  K. Zhao,et al.  Estrogen‐induced interaction between KLF5 and estrogen receptor (ER) suppresses the function of ER in ER‐positive breast cancer cells , 2010, International journal of cancer.

[111]  Min-young Lee,et al.  KLF5 enhances SREBP-1 action in androgen-dependent induction of fatty acid synthase in prostate cancer cells. , 2009, The Biochemical journal.

[112]  V. Yang,et al.  Krüppel-like factor 5 mediates cellular transformation during oncogenic KRAS-induced intestinal tumorigenesis. , 2008, Gastroenterology.

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[116]  Tumorigenesis and Neoplastic Progression Kru¨ppel-Like Factor 5 Is Not Required for K-Ras G12D Lung Tumorigenesis, but Represses ABCG2 Expression and Is Associated with Better Disease-Specific Survival , 2022 .