The Experts below are selected from a list of 20979 Experts worldwide ranked by ideXlab platform
Tommaso Russo - One of the best experts on this subject based on the ideXlab platform.
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Direct targets of KLF5 transcription factor contribute to the maintenance of mouse embryonic stem cell undifferentiated state
BMC Biology, 2010Co-Authors: Silvia Parisi, Luca Cozzuto, Carolina Tarantino, Fabiana Passaro, Simona Ciriello, Luigi Aloia, Dario Antonini, Vincenzo De Simone, Lucio Pastore, Tommaso RussoAbstract:Background A growing body of evidence has shown that Krüppel-like transcription factors play a crucial role in maintaining embryonic stem cell (ESC) pluripotency and in governing ESC fate decisions. Krüppel-like factor 5 (KLF5) appears to play a critical role in these processes, but detailed knowledge of the molecular mechanisms of this function is still not completely addressed. Results By combining genome-wide chromatin immunoprecipitation and microarray analysis, we have identified 161 putative primary targets of KLF5 in ESCs. We address three main points: (1) the relevance of the pathways governed by KLF5, demonstrating that suppression or constitutive expression of single KLF5 targets robustly affect the ESC undifferentiated phenotype; (2) the specificity of KLF5 compared to factors belonging to the same family, demonstrating that many KLF5 targets are not regulated by Klf2 and Klf4; and (3) the specificity of KLF5 function in ESCs, demonstrated by the significant differences between KLF5 targets in ESCs compared to adult cells, such as keratinocytes. Conclusions Taken together, these results, through the definition of a detailed list of KLF5 transcriptional targets in mouse ESCs, support the important and specific functional role of KLF5 in the maintenance of the undifferentiated ESC phenotype. See: http://www.biomedcental.com/1741-7007/8/125
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Direct targets of KLF5 transcription factor contribute to the maintenance of mouse embryonic stem cell undifferentiated state
BMC biology, 2010Co-Authors: Silvia Parisi, Luca Cozzuto, Carolina Tarantino, Fabiana Passaro, Simona Ciriello, Luigi Aloia, Dario Antonini, Vincenzo De Simone, Lucio Pastore, Tommaso RussoAbstract:A growing body of evidence has shown that Kruppel-like transcription factors play a crucial role in maintaining embryonic stem cell (ESC) pluripotency and in governing ESC fate decisions. Kruppel-like factor 5 (KLF5) appears to play a critical role in these processes, but detailed knowledge of the molecular mechanisms of this function is still not completely addressed. By combining genome-wide chromatin immunoprecipitation and microarray analysis, we have identified 161 putative primary targets of KLF5 in ESCs. We address three main points: (1) the relevance of the pathways governed by KLF5, demonstrating that suppression or constitutive expression of single KLF5 targets robustly affect the ESC undifferentiated phenotype; (2) the specificity of KLF5 compared to factors belonging to the same family, demonstrating that many KLF5 targets are not regulated by Klf2 and Klf4; and (3) the specificity of KLF5 function in ESCs, demonstrated by the significant differences between KLF5 targets in ESCs compared to adult cells, such as keratinocytes. Taken together, these results, through the definition of a detailed list of KLF5 transcriptional targets in mouse ESCs, support the important and specific functional role of KLF5 in the maintenance of the undifferentiated ESC phenotype. See: http://www.biomedcental.com/1741-7007/8/125
Masatsugu Ema - One of the best experts on this subject based on the ideXlab platform.
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KLF5 suppresses ERK signaling in mouse pluripotent stem cells
PloS one, 2018Co-Authors: Takuya Azami, Hyojung Jeon, Tsuyoshi Waku, Satoru Takahashi, Hitoshi Niwa, Ken Matsumoto, Masafumi Muratani, Masatsugu EmaAbstract:Mouse embryonic stem cells (ESCs) are pluripotent stem cells, which have the ability to differentiate into all three germ layers: mesoderm, endoderm, and ectoderm. Proper levels of phosphorylated extracellular signal-regulated kinase (pERK) are critical for maintaining pluripotency, as elevated pERK evoked by fibroblast growth factor (FGF) receptor activation results in differentiation of ESCs, while, conversely, reduction of pERK by a MEK inhibitor maintains a pluripotent ground state. However, mechanisms underlying proper control of pERK levels in mouse ESCs are not fully understood. Here, we find that KLF5, a Kruppel-like transcription factor family member, is a component of pERK regulation in mouse ESCs. We show that ERK signaling is overactivated in KLF5-KO ESCs and the overactivated ERK in KLF5-KO ESCs is suppressed by the introduction of KLF5, but not Klf2 or Klf4, indicating a unique role for KLF5 in ERK suppression. Moreover, KLF5 regulates Spred1, a negative regulator of the FGF-ERK pathway. KLF5 also facilitates reprogramming of EpiSCs into a naive state in combination with a glycogen synthase kinase 3 inhibitor and LIF, and in place of a MEK inhibitor. Taken together, these results show for the first time that KLF5 has a unique role suppressing ERK activity in mouse ESCs.
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comprehensive identification of kruppel like factor family members contributing to the self renewal of mouse embryonic stem cells and cellular reprogramming
PLOS ONE, 2016Co-Authors: Hyojung Jeon, Tsuyoshi Waku, Takuya Azami, Le Tran Phuc Khoa, Jun Yanagisawa, Satoru Takahashi, Masatsugu EmaAbstract:Pluripotency is maintained in mouse embryonic stem (ES) cells and is induced from somatic cells by the activation of appropriate transcriptional regulatory networks. Kruppel-like factor gene family members, such as Klf2, Klf4 and KLF5, have important roles in maintaining the undifferentiated state of mouse ES cells as well as in cellular reprogramming, yet it is not known whether other Klf family members exert self-renewal and reprogramming functions when overexpressed. In this study, we examined whether overexpression of any representative Klf family member, such as Klf1-Klf10, would be sufficient for the self-renewal of mouse ES cells. We found that only Klf2, Klf4, and KLF5 produced leukemia inhibitory factor (LIF)-independent self-renewal, although most KLF proteins, if not all, have the ability to occupy the regulatory regions of Nanog, a critical Klf target gene. We also examined whether overexpression of any of Klf1-Klf10 would be sufficient to convert epiblast stem cells into a naive pluripotent state and found that KLF5 had such reprogramming ability, in addition to Klf2 and Klf4. We also delineated the functional domains of the Klf2 protein for LIF-independent self-renewal and reprogramming. Interestingly, we found that both the N-terminal transcriptional activation and C-terminal zinc finger domains were indispensable for this activity. Taken together, our comprehensive analysis provides new insight into the contribution of Klf family members to mouse ES self-renewal and cellular reprogramming.
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kruppel like factor 5 is essential for blastocyst development and the normal self renewal of mouse escs
Cell Stem Cell, 2008Co-Authors: Masatsugu Ema, Hitoshi Niwa, Daisuke Mori, Yoshikazu Hasegawa, Yojiro Yamanaka, Seiji Hitoshi, Junsei Mimura, Yoh Ichi Kawabe, Tomohiro Hosoya, Masanobu MoritaAbstract:The transcription factor Klf4 has demonstrated activity in the reprogramming of somatic cells to a pluripotent state, but the molecular mechanism of this process remains unknown. It is, therefore, of great interest to understand the functional role of Klf4 and related genes in ESC regulation. Here, we show that homozygous disruption of KLF5 results in the failure of ESC derivation from ICM cells and early embryonic lethality due to an implantation defect. KLF5 KO ESCs show increased expression of several differentiation marker genes and frequent, spontaneous differentiation. Conversely, overexpression of KLF5 in ESCs suppressed the expression of differentiation marker genes and maintained pluripotency in the absence of LIF. Our results also suggest that KLF5 regulates ESC proliferation by promoting phosphorylation of Akt1 via induction of Tcl1. These results, therefore, provide new insights into the functional and mechanistic role of KLF5 in regulation of pluripotency.
Silvia Parisi - One of the best experts on this subject based on the ideXlab platform.
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Direct targets of KLF5 transcription factor contribute to the maintenance of mouse embryonic stem cell undifferentiated state
BMC Biology, 2010Co-Authors: Silvia Parisi, Luca Cozzuto, Carolina Tarantino, Fabiana Passaro, Simona Ciriello, Luigi Aloia, Dario Antonini, Vincenzo De Simone, Lucio Pastore, Tommaso RussoAbstract:Background A growing body of evidence has shown that Krüppel-like transcription factors play a crucial role in maintaining embryonic stem cell (ESC) pluripotency and in governing ESC fate decisions. Krüppel-like factor 5 (KLF5) appears to play a critical role in these processes, but detailed knowledge of the molecular mechanisms of this function is still not completely addressed. Results By combining genome-wide chromatin immunoprecipitation and microarray analysis, we have identified 161 putative primary targets of KLF5 in ESCs. We address three main points: (1) the relevance of the pathways governed by KLF5, demonstrating that suppression or constitutive expression of single KLF5 targets robustly affect the ESC undifferentiated phenotype; (2) the specificity of KLF5 compared to factors belonging to the same family, demonstrating that many KLF5 targets are not regulated by Klf2 and Klf4; and (3) the specificity of KLF5 function in ESCs, demonstrated by the significant differences between KLF5 targets in ESCs compared to adult cells, such as keratinocytes. Conclusions Taken together, these results, through the definition of a detailed list of KLF5 transcriptional targets in mouse ESCs, support the important and specific functional role of KLF5 in the maintenance of the undifferentiated ESC phenotype. See: http://www.biomedcental.com/1741-7007/8/125
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Direct targets of KLF5 transcription factor contribute to the maintenance of mouse embryonic stem cell undifferentiated state
BMC biology, 2010Co-Authors: Silvia Parisi, Luca Cozzuto, Carolina Tarantino, Fabiana Passaro, Simona Ciriello, Luigi Aloia, Dario Antonini, Vincenzo De Simone, Lucio Pastore, Tommaso RussoAbstract:A growing body of evidence has shown that Kruppel-like transcription factors play a crucial role in maintaining embryonic stem cell (ESC) pluripotency and in governing ESC fate decisions. Kruppel-like factor 5 (KLF5) appears to play a critical role in these processes, but detailed knowledge of the molecular mechanisms of this function is still not completely addressed. By combining genome-wide chromatin immunoprecipitation and microarray analysis, we have identified 161 putative primary targets of KLF5 in ESCs. We address three main points: (1) the relevance of the pathways governed by KLF5, demonstrating that suppression or constitutive expression of single KLF5 targets robustly affect the ESC undifferentiated phenotype; (2) the specificity of KLF5 compared to factors belonging to the same family, demonstrating that many KLF5 targets are not regulated by Klf2 and Klf4; and (3) the specificity of KLF5 function in ESCs, demonstrated by the significant differences between KLF5 targets in ESCs compared to adult cells, such as keratinocytes. Taken together, these results, through the definition of a detailed list of KLF5 transcriptional targets in mouse ESCs, support the important and specific functional role of KLF5 in the maintenance of the undifferentiated ESC phenotype. See: http://www.biomedcental.com/1741-7007/8/125
Jin-tang Dong - One of the best experts on this subject based on the ideXlab platform.
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HDAC-mediated deacetylation of KLF5 associates with its proteasomal degradation.
Biochemical and biophysical research communications, 2018Co-Authors: Ran Tao, Baotong Zhang, Jamie L. King, Ruoyu Tian, Siyuan Xia, Cara R. Schiavon, Jin-tang DongAbstract:Kruppel-like factor 5 (KLF5) is a basic transcription factor that regulates diverse cellular processes during tumor development. Acetylation of KLF5 at lysine 369 (K369) reverses its function from promoting to suppressing cell proliferation and tumor growth. In this study, we examined the regulation of KLF5 by histone deacetylases in the prostate cancer cell line DU 145. While confirming the functions of HDAC1/2 in KLF5 deacetylation and the promotion of cell proliferation, we found that the knockdown of HDAC1/2 upregulated KLF5 protein but not KLF5 mRNA, and the increase in KLF5 protein level by silencing HDAC1/2 was at least in part due to decreased proteasomal degradation. Deacetylase activity was required for HDAC1/2-mediated KLF5 degradation, and mutation of KLF5 to an acetylation-mimicking form prevented its degradation, even though the mutation did not affect the binding of KLF5 with HDAC1/2. Mutation of K369 to arginine, which prevents acetylation, did not affect the binding of KLF5 to HDAC1 or the response of KLF5 to HDAC1/2-promoted degradation. These findings provide a novel mechanistic association between the acetylation status of KLF5 and its protein stability. They also suggest that maintaining KLF5 in a deacetylated form may be an important mechanism by which KLF5 and HDACs promote cell proliferation and tumor growth.
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KLF5 promotes breast cell survival partially through fibroblast growth factor binding protein 1 perk mediated dual specificity mkp 1 protein phosphorylation and stabilization
Journal of Biological Chemistry, 2009Co-Authors: Rong Liu, Jin-tang Dong, Zhongmei Zhou, Hanqiu Zheng, Ceshi ChenAbstract:Krupple-like transcription factor 5 (KLF5) is a zinc-finger transcription factor promoting cell survival and tumorigenesis in multiple cancers. A high expression level of KLF5 has been shown to be associated with shorter breast cancer patient survival. However, the role of KLF5 and mechanism of KLF5 actions in breast cancer remain unclear. In this study, we found that KLF5 knockdown by small interfering RNA in two breast cell lines, MCF10A and BT20, induces apoptosis. Interestingly, a pro-survival phosphatase, dual specificity mitogen-activated protein kinase phosphatase 1 (MKP-1), is down-regulated by KLF5 ablation. Consistently, KLF5 overexpression increases the MKP-1 protein expression in Hs578T and MCF7. We further found that MKP-1 is essential and sufficient for KLF5 to promote breast cell survival. However, MKP-1 is not a KLF5 direct transcription target because the MKP-1 mRNA level is not regulated by KLF5. By cycloheximide chase assays, we found that KLF5 decreases MKP-1 protein degradation via activating the ERK signaling. Inhibition of pERK by the pharmacological inhibitor U0126 specifically blocks KLF5-induced MKP-1 phosphorylation and stabilization. Additionally, constitutive activation of ERK by constitutively activated MEK1 rescues the KLF5 depletion-induced MKP-1 down-regulation. Consistently, the phosphorylation-deficient MKP-1 mutant cannot be stabilized by KLF5. Finally, the activation of ERK by KLF5 is very likely through the KLF5 direct target gene FGF-BP in breast cells. These findings suggest that KLF5 is a pro-survival factor that promotes breast cell survival partially through pERK-mediated MKP-1 phosphorylation and stabilization. The KLF5-FGF-BP-pERK-MKP-1 signaling axis may provide new therapeutic targets for invasive breast cancer.
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pro proliferative factor KLF5 becomes anti proliferative in epithelial homeostasis upon signaling mediated modification
Journal of Biological Chemistry, 2009Co-Authors: Peng Guo, Xueyuan Dong, Xiaohui Zhang, Kewen Zhao, Xiaodong Sun, Jin-tang DongAbstract:During epithelial homeostasis, stem cells divide to produce progenitor cells, which not only proliferate to generate the cell mass but also respond to cellular signaling to transition from a proliferative state to a differentiation state. Such a transition involves functional alterations of transcriptional factors, yet the underlying molecular mechanisms are poorly understood. Recent studies have implicated Kruppel-like factors (KLFs) including KLF5 in the renewal and maintenance of stem/progenitor cells. Here we demonstrate that the pro-proliferative factor KLF5 becomes anti-proliferative upon TGFβ-mediated acetylation in an in vitro model of epithelial homeostasis. In the HaCaT epidermal cell line treated with or without TGFβ, we found that KLF5 was not only essential for cell proliferation, it was also indispensable for TGFβ-induced anti-proliferation in these cells. KLF5 inhibited the expression of p15 (CDKN2B), a cell cycle inhibitor, without TGFβ, but became a coactivator in TGFβ-induced p15 expression in the same cells. Mechanistically, TGFβ recruited acetylase p300 to acetylate KLF5, and acetylation in turn altered the binding of KLF5 to p15 promoter, resulting in the reversal of KLF5 function. These studies not only demonstrate that a basic transcription factor can be both pro-proliferation and anti-proliferation in epithelial homeostasis, they also present a unique mechanism for how transcriptional regulation changes during the transition from proliferation to inhibition of proliferation. Furthermore, they establish KLF5 as an essential cofactor for TGFβ signaling.
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Regulation of KLF5 involves the Sp1 transcription factor in human epithelial cells
Gene, 2004Co-Authors: Ceshi Chen, Yingfa Zhou, Kristen B. Otto, Zhongmei Zhou, Jin-tang DongAbstract:Abstract Human Kruppel-like factor 5 (hKLF5) is a transcription factor with a potential tumor suppressor function in prostate and breast cancers. In the majority of cancer samples examined, a significant loss of expression for KLF5 has been detected. Whereas hemizygous deletion appears to be responsible for KLF5's reduced expression in about half of the cases, the mechanism for reduction is unknown in the remaining half; gene promoter methylation does not appear to be involved. In this report, we studied the regulation of KLF5 and cloned and functionally characterized a 1944-bp fragment of the 5′-flanking region of the hKLF5 gene. Several mitogens as well as global demethylation induced the expression of KLF5, implicating multiple factors in the regulation of KLF5. KLF5's promoter lacks a TATA box and has a GC-rich region. Deletion mapping in combination with promoter activity assay showed that multiple cis-elements are involved in the transcriptional regulation of KLF5, some of which may play a repressor role whereas some others play an enhancer role. The Sp1 site between position −239 and −219 is essential for a basal promoter activity. Deletion or mutations of this Sp1 site significantly reduced promoter activity in several epithelial cell lines. Electrophoretic mobility shift assays (EMSAs) revealed that the Sp1 site binds Sp1 protein in nucleic extracts of different cell lines. In addition, overexpression of Sp1 protein transactivates KLF5 promoter activity. These findings suggest that Sp1 is a key transcription factor in KLF5's dynamic transcriptional regulation.
Ceshi Chen - One of the best experts on this subject based on the ideXlab platform.
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The Roles and Regulation of the KLF5 Transcription Factor in Cancers.
Cancer science, 2021Co-Authors: Yao Luo, Ceshi ChenAbstract:Krüppel-like factor 5 (KLF5) is a member of the KLF family. Recent studies suggest that KLF5 regulates the expression of a large number of new target genes and participates in diverse cellular functions, such as stemness, proliferation, apoptosis, autophagy, and migration. In response to multiple signaling pathways, a variety of transcriptional modulation and posttranslational modifications affect the expression level and activity of KLF5. Several transgenic mouse models have revealed the physiological and pathological functions of KLF5 in different cancers. Studies of KLF5 will provide prognostic biomarkers, therapeutic targets, and potential drugs for cancers.
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TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes breast cell proliferation and tumorigenesis.
Carcinogenesis, 2011Co-Authors: Dong Zhao, Xu Zhi, Zhongmei Zhou, Ceshi ChenAbstract:Kruppel-like factor 5 (KLF5) is a PY motif-containing transcription factor promoting breast cell proliferation. The KLF5 protein is rapidly degraded through the proteasome after ubiquitination by E3 ubiquitin ligases, such as WWP1 and SCF(Fbw7). In this study, we demonstrated that a transcriptional co-activator with the PDZ-binding motif (TAZ) upregulated the KLF5 expression through antagonizing the WWP1-, but not Fbw7-, mediated KLF5 ubiquitination and degradation. TAZ interacted with KLF5 through the WW domain of TAZ and the PY motif of KLF5, which is the binding site for WWP1. TAZ inhibited WWP1-KLF5 protein interaction and WWP1-mediated KLF5 ubiquitination and degradation in a WW domain-dependent manner. Overexpression of TAZ upregulated the protein levels of KLF5 and FGF-BP, which is a well-established KLF5 target gene. In addition, depletion of TAZ in both 184A1 and HCC1937 breast cells downregulated protein levels of KLF5 and FGF-BP and inhibited cell growth. Furthermore, stable depletion of either TAZ or KLF5 significantly suppressed HCC1937 xenograft growth in immunodeficient mice. Knockdown of LATS1, a TAZ upstream inhibitory kinase, up-regulated the protein levels of KLF5 and FGF-BP in 184A1 and promoted cell growth through TAZ. Finally, both KLF5 and TAZ were co-expressed in a subset of estrogen receptor α-negative breast cell lines. These results, for the first time, suggest that TAZ promotes breast cell growth partially through protecting KLF5 from WWP1-mediated degradation and enhancing KLF5's activities.
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KLF5 promotes breast cell survival partially through fibroblast growth factor binding protein 1 perk mediated dual specificity mkp 1 protein phosphorylation and stabilization
Journal of Biological Chemistry, 2009Co-Authors: Rong Liu, Jin-tang Dong, Zhongmei Zhou, Hanqiu Zheng, Ceshi ChenAbstract:Krupple-like transcription factor 5 (KLF5) is a zinc-finger transcription factor promoting cell survival and tumorigenesis in multiple cancers. A high expression level of KLF5 has been shown to be associated with shorter breast cancer patient survival. However, the role of KLF5 and mechanism of KLF5 actions in breast cancer remain unclear. In this study, we found that KLF5 knockdown by small interfering RNA in two breast cell lines, MCF10A and BT20, induces apoptosis. Interestingly, a pro-survival phosphatase, dual specificity mitogen-activated protein kinase phosphatase 1 (MKP-1), is down-regulated by KLF5 ablation. Consistently, KLF5 overexpression increases the MKP-1 protein expression in Hs578T and MCF7. We further found that MKP-1 is essential and sufficient for KLF5 to promote breast cell survival. However, MKP-1 is not a KLF5 direct transcription target because the MKP-1 mRNA level is not regulated by KLF5. By cycloheximide chase assays, we found that KLF5 decreases MKP-1 protein degradation via activating the ERK signaling. Inhibition of pERK by the pharmacological inhibitor U0126 specifically blocks KLF5-induced MKP-1 phosphorylation and stabilization. Additionally, constitutive activation of ERK by constitutively activated MEK1 rescues the KLF5 depletion-induced MKP-1 down-regulation. Consistently, the phosphorylation-deficient MKP-1 mutant cannot be stabilized by KLF5. Finally, the activation of ERK by KLF5 is very likely through the KLF5 direct target gene FGF-BP in breast cells. These findings suggest that KLF5 is a pro-survival factor that promotes breast cell survival partially through pERK-mediated MKP-1 phosphorylation and stabilization. The KLF5-FGF-BP-pERK-MKP-1 signaling axis may provide new therapeutic targets for invasive breast cancer.
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Regulation of KLF5 involves the Sp1 transcription factor in human epithelial cells
Gene, 2004Co-Authors: Ceshi Chen, Yingfa Zhou, Kristen B. Otto, Zhongmei Zhou, Jin-tang DongAbstract:Abstract Human Kruppel-like factor 5 (hKLF5) is a transcription factor with a potential tumor suppressor function in prostate and breast cancers. In the majority of cancer samples examined, a significant loss of expression for KLF5 has been detected. Whereas hemizygous deletion appears to be responsible for KLF5's reduced expression in about half of the cases, the mechanism for reduction is unknown in the remaining half; gene promoter methylation does not appear to be involved. In this report, we studied the regulation of KLF5 and cloned and functionally characterized a 1944-bp fragment of the 5′-flanking region of the hKLF5 gene. Several mitogens as well as global demethylation induced the expression of KLF5, implicating multiple factors in the regulation of KLF5. KLF5's promoter lacks a TATA box and has a GC-rich region. Deletion mapping in combination with promoter activity assay showed that multiple cis-elements are involved in the transcriptional regulation of KLF5, some of which may play a repressor role whereas some others play an enhancer role. The Sp1 site between position −239 and −219 is essential for a basal promoter activity. Deletion or mutations of this Sp1 site significantly reduced promoter activity in several epithelial cell lines. Electrophoretic mobility shift assays (EMSAs) revealed that the Sp1 site binds Sp1 protein in nucleic extracts of different cell lines. In addition, overexpression of Sp1 protein transactivates KLF5 promoter activity. These findings suggest that Sp1 is a key transcription factor in KLF5's dynamic transcriptional regulation.