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Nanping Wang - One of the best experts on this subject based on the ideXlab platform.

  • s nitrosation impairs KLF4 activity and instigates endothelial dysfunction in pulmonary arterial hypertension
    Redox biology, 2019
    Co-Authors: Yiqian Ban, Chang Chen, Yuying Zhang, Yahan Liu, Lei Xiao, Shaoliang Chen, Beilei Zhao, Nanping Wang
    Abstract:

    Kruppel-like factor 4 (KLF4) is a transcription factor with conserved zinc finger domains. As an essential regulator of vascular homeostasis, KLF4 exerts a protective effect in endothelial cells (ECs), including regulating vasodilation, inflammation, coagulation and oxidative stress. However, the underlying mechanisms modifying KLF4 activity in mediating vascular function remain poorly understood. Recently, essential roles for S-nitrosation have been implicated in many pathophysiologic processes of cardiovascular disease. Here, we demonstrated that KLF4 could undergo S-nitrosation in response to nitrosative stress in ECs, leading to the decreased nuclear localization with compromised transactivity. Mass-spectrometry and site-directed mutagenesis revealed that S-nitrosation modified KLF4 predominantly at Cys437. Functionally, KLF4 dependent vasodilatory response was impaired after S-nitrosoglutathione (GSNO) treatment. In ECs, endothelin-1 (ET-1) induced KLF4 S-nitrosation, which was inhibited by an endothelin receptor antagonist Bosentan. In hypoxia-induced rat model of pulmonary arterial hypertension (PAH), S-nitrosated KLF4 (SNO-KLF4) was significantly increased in lung tissues, along with decreased nuclear localization of KLF4. In summary, we demonstrated that S-nitrosation is a novel mechanism for the post-translational modification of KLF4 in ECs. Moreover, these findings suggested that KLF4 S-nitrosation may be implicated in the pathogenesis of vascular dysfunction and diseases such as PAH.

  • S-nitrosation impairs KLF4 activity and instigates endothelial dysfunction in pulmonary arterial hypertension
    Elsevier, 2019
    Co-Authors: Yiqian Ban, Chang Chen, Yuying Zhang, Yahan Liu, Lei Xiao, Shaoliang Chen, Beilei Zhao, Nanping Wang
    Abstract:

    Krüppel-like factor 4 (KLF4) is a transcription factor with conserved zinc finger domains. As an essential regulator of vascular homeostasis, KLF4 exerts a protective effect in endothelial cells (ECs), including regulating vasodilation, inflammation, coagulation and oxidative stress. However, the underlying mechanisms modifying KLF4 activity in mediating vascular function remain poorly understood. Recently, essential roles for S-nitrosation have been implicated in many pathophysiologic processes of cardiovascular disease. Here, we demonstrated that KLF4 could undergo S-nitrosation in response to nitrosative stress in ECs, leading to the decreased nuclear localization with compromised transactivity. Mass-spectrometry and site-directed mutagenesis revealed that S-nitrosation modified KLF4 predominantly at Cys437. Functionally, KLF4 dependent vasodilatory response was impaired after S-nitrosoglutathione (GSNO) treatment. In ECs, endothelin-1 (ET-1) induced KLF4 S-nitrosation, which was inhibited by an endothelin receptor antagonist Bosentan. In hypoxia-induced rat model of pulmonary arterial hypertension (PAH), S-nitrosated KLF4 (SNO-KLF4) was significantly increased in lung tissues, along with decreased nuclear localization of KLF4. In summary, we demonstrated that S-nitrosation is a novel mechanism for the post-translational modification of KLF4 in ECs. Moreover, these findings suggested that KLF4 S-nitrosation may be implicated in the pathogenesis of vascular dysfunction and diseases such as PAH. Keywords: Krüppel-like factor 4, S-nitrosation, Endothelium, Pulmonary arterial hypertensio

Jennifer A. Mitchell - One of the best experts on this subject based on the ideXlab platform.

  • KLF4 protein stability regulated by interaction with pluripotency transcription factors overrides transcriptional control
    Genes & Development, 2019
    Co-Authors: Navroop K. Dhaliwal, Luis E Abatti, Jennifer A. Mitchell
    Abstract:

    Embryonic stem (ES) cells are regulated by a network of transcription factors that maintain the pluripotent state. Differentiation relies on down-regulation of pluripotency transcription factors disrupting this network. While investigating transcriptional regulation of the pluripotency transcription factor Kruppel-like factor 4 (KLF4), we observed that homozygous deletion of distal enhancers caused a 17-fold decrease in KLF4 transcript but surprisingly decreased protein levels by less than twofold, indicating that posttranscriptional control of KLF4 protein overrides transcriptional control. The lack of sensitivity of KLF4 to transcription is due to high protein stability (half-life >24 h). This stability is context-dependent and is disrupted during differentiation, as evidenced by a shift to a half-life of <2 h. KLF4 protein stability is maintained through interaction with other pluripotency transcription factors (NANOG, SOX2, and STAT3) that together facilitate association of KLF4 with RNA polymerase II. In addition, the KLF4 DNA-binding and transactivation domains are required for optimal KLF4 protein stability. Posttranslational modification of KLF4 destabilizes the protein as cells exit the pluripotent state, and mutations that prevent this destabilization also prevent differentiation. These data indicate that the core pluripotency transcription factors are integrated by posttranslational mechanisms to maintain the pluripotent state and identify mutations that increase KLF4 protein stability while maintaining transcription factor function.

  • KLF4 protein stability regulated by interaction with pluripotency transcription factors overrides transcriptional control
    bioRxiv, 2019
    Co-Authors: Navroop K. Dhaliwal, Luis E Abatti, Jennifer A. Mitchell
    Abstract:

    Embryonic stem (ES) cells are regulated by a network of transcription factors which maintain the pluripotent state. Differentiation relies on downregulation of pluripotency transcription factors disrupting this network. While investigating transcriptional regulation of the pluripotency transcription factor KLF4, we observed homozygous deletion of distal enhancers caused 17 fold decrease in KLF4 transcript but surprisingly decreased protein levels by 24hr). This stability is context dependent and disrupted during differentiation, evidenced by a shift to a half-life of <2hr. KLF4 protein stability is maintained through interaction with other pluripotency transcription factors (NANOG, SOX2 and STAT3) that together facilitate association of KLF4 with RNA polymerase II. In addition, the KLF4 DNA binding and transactivation domains are required for KLF4 protein stability. Post-translational modification of KLF4 destabilizes the protein as cells exit the pluripotent state and mutations that prevent this destabilization also prevent differentiation. These data indicate the core pluripotency transcription factors are integrated by post-translational mechanisms to maintain the pluripotent state, and identify mutations that increase KLF4 protein stability while maintaining transcription factor function.

  • KLF4 nuclear export requires erk activation and initiates exit from naive pluripotency
    Stem cell reports, 2018
    Co-Authors: Navroop K. Dhaliwal, Kamelia Miri, Scott Davidson, Hala Tamim El Jarkass, Jennifer A. Mitchell
    Abstract:

    Cooperative action of a transcription factor complex containing OCT4, SOX2, NANOG, and KLF4 maintains the naive pluripotent state; however, less is known about the mechanisms that disrupt this complex, initiating exit from pluripotency. We show that, as embryonic stem cells (ESCs) exit pluripotency, KLF4 protein is exported from the nucleus causing rapid decline in Nanog and KLF4 transcription; as a result, KLF4 is the first pluripotency transcription factor removed from transcription-associated complexes during differentiation. KLF4 nuclear export requires ERK activation, and phosphorylation of KLF4 by ERK initiates interaction of KLF4 with nuclear export factor XPO1, leading to KLF4 export. Mutation of the ERK phosphorylation site in KLF4 (S132) blocks KLF4 nuclear export, the decline in Nanog, KLF4, and Sox2 mRNA, and differentiation. These findings demonstrate that relocalization of KLF4 to the cytoplasm is a critical first step in exit from the naive pluripotent state and initiation of ESC differentiation.

  • KLF4 Nuclear Export Requires ERK Activation and Initiates Exit from Naive Pluripotency
    Elsevier, 2018
    Co-Authors: Navroop K. Dhaliwal, Kamelia Miri, Scott Davidson, Hala Tamim El Jarkass, Jennifer A. Mitchell
    Abstract:

    Summary: Cooperative action of a transcription factor complex containing OCT4, SOX2, NANOG, and KLF4 maintains the naive pluripotent state; however, less is known about the mechanisms that disrupt this complex, initiating exit from pluripotency. We show that, as embryonic stem cells (ESCs) exit pluripotency, KLF4 protein is exported from the nucleus causing rapid decline in Nanog and KLF4 transcription; as a result, KLF4 is the first pluripotency transcription factor removed from transcription-associated complexes during differentiation. KLF4 nuclear export requires ERK activation, and phosphorylation of KLF4 by ERK initiates interaction of KLF4 with nuclear export factor XPO1, leading to KLF4 export. Mutation of the ERK phosphorylation site in KLF4 (S132) blocks KLF4 nuclear export, the decline in Nanog, KLF4, and Sox2 mRNA, and differentiation. These findings demonstrate that relocalization of KLF4 to the cytoplasm is a critical first step in exit from the naive pluripotent state and initiation of ESC differentiation. : Dhaliwal and colleagues show that KLF4 is exported from the nucleus to initiate embryonic stem cell differentiation. KLF4 nuclear export is caused by FGF-MEK-ERK signaling whereby activated ERK phosphorylates KLF4, allowing interaction with nuclear export factor Xportin1. Blocking KLF4 nuclear export prevents embryonic stem cell exit from naive pluripotency and slows development of the embryo. Keywords: KLF4, embryonic stem cell, nuclear export, pluripotency, XPO1, ERK, transcription factor, proximity ligation amplificatio

Keping Xie - One of the best experts on this subject based on the ideXlab platform.

  • KLF4 is essential for induction of cellular identity change and acinar to ductal reprogramming during early pancreatic carcinogenesis
    Cancer Cell, 2016
    Co-Authors: Daoyan Wei, Liang Wang, Yongmin Yan, Zhiliang Jia, Mihai Gagea, Xiangsheng Zuo, Xiangyu Kong, Suyun Huang, Keping Xie
    Abstract:

    Understanding the molecular mechanisms of tumor initiation has significant impact on early cancer detection and intervention. To define the role of KLF4 in pancreatic ductal adenocarcinoma (PDA) initiation, we used molecular biological analyses and mouse models of KLF4 gain- and loss-of-function and mutant Kras. KLF4 is upregulated in and required for acinar-to-ductal metaplasia. KLF4 ablation drastically attenuates the formation of pancreatic intraepithelial neoplasia induced by mutant Kras(G12D), whereas upregulation of KLF4 does the opposite. Mutant KRAS and cellular injuries induce KLF4 expression, and ectopic expression of KLF4 in acinar cells reduces acinar lineage- and induces ductal lineage-related marker expression. These results demonstrate that KLF4 induces ductal identity in PanIN initiation and may be a potential target for prevention of PDA initiation.

  • a novel KLF4 ldha signaling pathway regulates aerobic glycolysis in and progression of pancreatic cancer
    Clinical Cancer Research, 2014
    Co-Authors: Daoyan Wei, Zhiliang Jia, Min Shi, Jiujie Cui, Jun Zhang, Zhenggang Zhu, Yong Gao, Keping Xie
    Abstract:

    Purpose: Kruppel-like factor 4 (KLF4) is a transcription factor and putative tumor suppressor. However, little is known about its effect on aerobic glycolysis in pancreatic tumors. Therefore, we investigated the clinical significance, biologic effects, and mechanisms of dysregulated KLF4 signaling in aerobic glycolysis in pancreatic cancer cells. Experimental Design: Expression of KLF4 and lactate dehydrogenase A (LDHA) in 70 primary pancreatic tumors and 10 normal pancreatic tissue specimens was measured. Also, the underlying mechanisms of altered KLF4 expression and its impact on aerobic glycolysis in pancreatic cancer cells were investigated. Results: We found a negative correlation between KLF4 and LDHA expression in pancreatic cancer cells and tissues and that their expression was associated with clinicopathologic features of pancreatic cancer. KLF4 underexpression and LDHA overexpression were correlated with disease stage and tumor differentiation. Experimentally, KLF4 overexpression significantly attenuated the aerobic glycolysis in and growth of pancreatic cancer cells both in vitro and in orthotopic mouse models, whereas knockdown of KLF4 expression had the opposite effect. Enforced KLF4 expression decreased LDHA expression, whereas small interfering RNA–mediated knockdown of KLF4 expression had the opposite effect. Mechanistically, KLF4 bound directly to the promoter regions of the LDHA gene and negatively regulated its transcription activity. Conclusions: Dysregulated signaling in this novel KLF4/LDHA pathway significantly impacts aerobic glycolysis in and development and progression of pancreatic cancer. Clin Cancer Res; 20(16); 4370–80. ©2014 AACR .

  • dysregulated kruppel like factor 4 and vitamin d receptor signaling contribute to progression of hepatocellular carcinoma
    Gastroenterology, 2012
    Co-Authors: Yong Gao, Daoyan Wei, Zhiliang Jia, Suyun Huang, Lopa Mishra, Kun Guo, Keping Xie
    Abstract:

    Background & Aims Kruppel-like factor 4 (KLF4) is a transcription factor and putative tumor suppressor. However, little is known about its effects in hepatocellular carcinogenesis. We investigated the clinical significance, biologic effects, and mechanisms of dysregulated KLF4 signaling. Methods We performed microarray analysis of hepatocellular carcinoma (HCC) tissues. We used molecular biology analyses and animal models to evaluate activation and function of KLF4-vitamin D receptor (VDR) pathway. Results Expression of KLF4 protein was decreased or lost in primary HCC samples, in particular, lymph node metastases, compared with normal liver tissues. Loss of KLF4 from primary tumors was significantly associated with reduced survival time and was identified as a prognostic marker. Most human HCC cell lines had losses or substantial decreases in levels of KLF4. Exogenous expression of KLF4 in HCC cells upregulated expression of mesenchymal-epithelial transition (MET) and inhibited their migration, invasion, and proliferation in vitro. When these cells were injected into mice, tumors grew more slowly and metastatsis was inhibited, compared with HCC cells that did not express KLF4. VDR is a direct transcriptional target of KLF4; we identified 2 sites in the VDR promoter that bound specifically to KLF4. Increased expression of VDR sensitized tumor cells to the inhibitory effects of vitamin D. Conclusions KLF4 binds to the promoter of VDR to regulate its expression; levels of KLF4 are reduced and levels of VDR are increased in HCC cell lines and primary tumor samples. Expression of KLF4 in HCC cells sensitizes them to the anti-proliferative effects of VD3. This pathway might be manipulated to prevent or treat liver cancer.

  • putative tumor suppressive function of kruppel like factor 4 in primary lung carcinoma
    Clinical Cancer Research, 2009
    Co-Authors: Wayne L Hofstetter, Yanbin Zhou, Abujiang Pataer, Li Wang, Keping Xie, Stephen G Swisher, Bingliang Fang
    Abstract:

    Purpose: Kruppel-like factor 4 (KLF4) is a zinc-finger protein that plays important roles in stem cells and the development of gastric cancers. However, the role of KLF4 in primary lung cancer is unknown. The purpose of this study is to determine possible roles of KLF4 in lung cancer. Experimental Design: The KLF4 expression in primary lung cancer tissues and case-matched normal lung tissues were determined by protein and mRNA analyses. The effects of KLF4 on cell proliferation, clonogenic formation, and cell cycle progression were determined in cultured lung cancer cells or bronchial epithelial cells after enforced KLF4 overexpression or small interfering RNA knockdown. The in vivo antitumor activity of KLF4 was evaluated by using stably transfected lung cancer cells and by adenovector-mediated gene delivery. The effect of KLF4 in regulating p21 and cyclin D1 was also evaluated. Results: KLF4 protein and mRNA levels were dramatically decreased in most primary lung tumors compared with in case-matched normal lung tissues. Enforced expression of KLF4 resulted in marked inhibition of cell growth and clonogenic formation. The tumor-suppressive effect of KLF4 was associated with its role in up-regulating p21 and down-regulating cyclin D1, leading to cell cycle arrest at the G 1 -S checkpoint. Knockdown of KLF4 promoted cell growth in immortalized human bronchial epithelial cells. The enforced expression of KLF4 gene to lung cancer cells by ex vivo transfection or adenovector-mediated gene transfer suppressed tumor growth in vivo . Conclusions: Our results suggest that KLF4 plays an important role in suppressing the growth of lung carcinoma. (Clin Cancer Res 2009;15(18):5688–95)

  • kruppel like factor 4 induces p27kip1 expression in and suppresses the growth and metastasis of human pancreatic cancer cells
    Cancer Research, 2008
    Co-Authors: Daoyan Wei, Zhiliang Jia, Masahsi Kanai, Keping Xie
    Abstract:

    The zinc finger transcription factor Kruppel-like factor 4 (KLF4) has been implicated in both tumor suppression and progression. However, its function in pancreatic cancer has not been well characterized. Here, we show that pancreatic cancer cell lines expressed various levels of KLF4 RNA and protein. Ectopic expression of KLF4 by FG and BxPC-3 pancreatic cancer cells resulted in cell cycle arrest and marked inhibition of cell growth in vitro and attenuation of tumor growth and metastasis in an orthotopic mouse model. Overexpression of KLF4 also led to significant induction of p27(Kip1) expression, at both the RNA and protein levels, in a dose- and time-dependent manner, indicating that KLF4 transcriptionally regulates the expression of p27(Kip1). Chromatin immunoprecipitation assays consistently showed that KLF4 protein physically interacts with the p27(Kip1) promoter. Promoter deletion and point mutation analyses indicated that a region between nucleotides -435 and -60 of the p27(Kip1) promoter and intact of the three KLF4-binding sites within that region were required for the full induction of p27(Kip1) promoter activity by KLF4. Our findings suggest that KLF4 transactivates p27(Kip1) expression and inhibits the growth and metastasis of human pancreatic cancer.

Vincent W. Yang - One of the best experts on this subject based on the ideXlab platform.

  • role of kruppel like factor 5 in the maintenance of the stem cell niche in the intestinal crypt
    Stem Cell and Translational Investigation, 2015
    Co-Authors: Jes G Kuruvilla, Amr M. Ghaleb, Agnieszka B. Bialkowska, Mandayam O Nandan, Vincent W. Yang
    Abstract:

    The intestinal epithelium is a tissue that undergoes continuous self-renewal initiated at the bottom of the crypts, which harbor the intestinal stem cell (ISC) pool.  The ISC pool is sub-divided into crypt base columnar (CBC) cells at the crypt bottom and label retention cells (LRC) at position +4 from the crypt bottom.  CBC cells are marked by Leucine-rich repeat-containing G-protein coupled receptor (Lgr5) while LRC cells are identified by several markers including Bmi1, mTert, Hopx, Lrig1, and Sox9.  Kruppel-like factors (KLFs) belong to a family of transcription factors that exert important physiological function in various tissues.  In the intestine, KLF4 is predominantly expressed in the terminally differentiated, non-proliferating cells lining the villus.  Its deletion in the adult mouse intestine results in perturbed homeostasis.  In contrast, KLF5 is expressed in actively proliferating cells of the intestinal crypt, including CBC cells and transit amplifying (TA) cells.  We recently investigated the effect of Klf5 deletion specifically from the Lgr5-expressing CBC cells in adult mouse intestine using an inducible Cre recombinase system.  Shortly (3-5 days) after Cre induction, proliferation of both CBC and TA cells ceased, which was accompanied by an increase in apoptosis in the crypt.  Beginning at two weeks following Cre induction, both Klf5 expression and proliferation re-appeared but without the re-emergence of Lgr5-positive CBC cells, which were eventually depleted by four months following induction. These findings indicate that KLF5 plays an important role in regulating proliferation and survival of CBC stem cells in the intestine.

  • notch inhibits expression of the kruppel like factor 4 tumor suppressor in the intestinal epithelium
    Molecular Cancer Research, 2008
    Co-Authors: Amr M. Ghaleb, Agnieszka B. Bialkowska, Gaurav Aggarwal, Mandayam O Nandan, Vincent W. Yang
    Abstract:

    The zinc finger-containing transcription factor, Kruppel-like factor 4 (KLF4), inhibits cell proliferation. An in vivo tumor-suppressive role for KLF4 is shown by the recent finding that KLF4 haploinsufficiency in ApcMin/+ mice promotes intestinal tumorigenesis. Studies also show that KLF4 is required for the terminal differentiation of goblet cells in the mouse intestine. The Notch signaling pathway suppresses goblet cell formation and is up-regulated in intestinal tumors. Here, we investigated the relationship between Notch signaling and KLF4 expression in intestinal epithelial cells. The rate of proliferation of HT29 human colon cancer cells was reduced when treated with the γ-secretase inhibitor dibenzazepine to inhibit Notch signaling or small interfering RNA directed against Notch. KLF4 levels were increased in dibenzazepine-treated or Notch small interfering RNA-treated cells. Conversely, overexpression of Notch in HT29 cells reduced KLF4 levels, suppressed KLF4 promoter activity, and increased proliferation rate. Treatment of ApcMin/+ mice with dibenzazepine resulted in a 50% reduction in the number of intestinal adenomas compared with the vehicle-treated group (P

  • haploinsufficiency of kruppel like factor 4 promotes adenomatous polyposis coli dependent intestinal tumorigenesis
    Cancer Research, 2007
    Co-Authors: Amr M. Ghaleb, Mandayam O Nandan, Jonathan P. Katz, Klaus H Kaestner, Beth B Mcconnell, Vincent W. Yang
    Abstract:

    The zinc finger transcription factor Kruppel-like factor 4 (KLF4) is frequently down-regulated in colorectal cancer. Previous studies showed that the expression of KLF4 was activated by the colorectal cancer tumor suppressor adenomatous polyposis coli (APC) and that KLF4 repressed the Wnt/β-catenin pathway. Here, we examined whether KLF4 plays a role in modulating intestinal tumorigenesis by comparing the tumor burdens in mice heterozygous for the ApcMin allele ( ApcMin/+ ) and those heterozygous for both the ApcMin and KLF4 alleles ( KLF4+/−/ApcMin/+ ). Between 10 and 20 weeks of age, KLF4+/−/ApcMin/+ mice developed, on average, 59% more intestinal adenomas than ApcMin/+ mice ( P < 0.0001). Immunohistochemical staining showed that KLF4 protein levels were lower in the normal-appearing intestinal tissues of KLF4+/−/ApcMin/+ mice compared with wild-type, KLF4+/− , or ApcMin/+ mice. In contrast, the levels of β-catenin and cyclin D1 were higher in the normal-appearing intestinal tissues of KLF4+/−/ApcMin/+ mice compared with the other three genotypes. KLF4 levels were further decreased in adenomas from both ApcMin/+ and KLF4+/−/ApcMin/+ mice compared with their corresponding normal-appearing tissues. Reverse transcription-PCR showed an inverse correlation between adenoma size and KLF4 mRNA levels in both KLF4+/−/ApcMin/+ and ApcMin/+ mice. There was also a progressive loss of heterozygosity of the wild-type Apc allele in adenomas with increasing size from KLF4+/−/ApcMin/+ and ApcMin/+ mice. Results from this study show that KLF4 plays an important role in promoting the development of intestinal adenomas in the presence of ApcMin mutation. [Cancer Res 2007;67(15):7147–54]

  • Overexpression of Krüppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity
    Oncogene, 2003
    Co-Authors: Duyen T Dang, Xinming Chen, Jing Feng, Michael Torbenson, Long H Dang, Vincent W. Yang
    Abstract:

    Krüppel-like factor 4 (KLF4) is a zinc-finger-containing transcription factor, the expression of which is enriched in the postmitotic cells of the intestinal epithelium. KLF4 is a target gene of the tumor suppressor adenomatous polyposis coli (APC). We sought to determine the role of KLF4 in suppressing the tumorigenecity of RKO colon cancer cells, which do not express KLF4. We utilized an established system in RKO cells, in which an inducible promoter controls expression of KLF4. Four independent assays were used to assess the effects of KLF4 induction on tumor cells. We find that KLF4 overexpression reduces colony formation, cell migration and invasion, and in vivo tumorigenecity. The mechanism of action of KLF4 does not involve apoptosis. These findings, along with our previous findings that KLF4 induces G1/S arrest, suggest that KLF4 is a cell cycle checkpoint protein that can reduce tumorigenecity of colon cancer cells.

  • the zinc finger transcription factor KLF4 is required for terminal differentiation of goblet cells in the colon
    Development, 2002
    Co-Authors: Jonathan P. Katz, Vincent W. Yang, Bree G. Goldstein, Nathalie Perreault, Catherine S Lee, Patricia A Labosky, Klaus H Kaestner
    Abstract:

    KLF4 (formerly GKLF) is a zinc-finger transcription factor expressed in the epithelia of the skin, lungs, gastrointestinal tract and several other organs. In vitro studies have suggested that KLF4 plays an important role in cell proliferation and/or differentiation. Mice homozygous for a null mutation in KLF4 die within 15 hours of birth and show selective perturbation of late-stage differentiation structures in the epidermis, but the function of KLF4 in the gastrointestinal tract has not been investigated. To address this issue, we have generated KLF4 –/– mice by homologous recombination in embryonic stem cells. In this study, we provide the first in vivo evidence that KLF4 is a goblet cell-specific differentiation factor in the colon. KLF4 –/– mice exhibit normal cell proliferation and cell death rates in the colon on postnatal day 1. However, KLF4 –/– mice demonstrate a 90% decrease in the number of goblet cells in the colon, show abnormal expression of the goblet cell-specific marker Muc2 by in situ hybridization, have abnormal staining of the colonic epithelium with Alcian Blue for acidic mucins, and lack normal goblet cell morphology by ultrastructural analysis. All other epithelial cell types are present in the colon of KLF4 –/– mice. In summary, KLF4 plays a crucial role in colonic epithelial cell differentiation in vivo.

Jonathan P. Katz - One of the best experts on this subject based on the ideXlab platform.

  • the kruppel like factor KLF4 is a critical regulator of monocyte differentiation
    The EMBO Journal, 2007
    Co-Authors: Mark W Feinberg, Jonathan P. Katz, Akm Khyrul Wara, Zhuoxiao Cao, Maria A Lebedeva, Frank Rosenbauer, Hiromi Iwasaki, Hideyo Hirai, Richard L Haspel, Susan Gray
    Abstract:

    Monocyte differentiation involves the participation of lineage-restricted transcription factors, although the mechanisms by which this process occurs are incompletely defined. Within the hematopoietic system, members of the Kruppel-like family of factors (KLFs) play essential roles in erythrocyte and T lymphocyte development. Here we show that KLF4/GKLF is expressed in a monocyte-restricted and stage-specific pattern during myelopoiesis and functions to promote monocyte differentiation. Overexpression of KLF4 in HL-60 cells confers the characteristics of mature monocytes. Conversely, KLF4 knockdown blocked phorbol ester-induced monocyte differentiation. Forced expression of KLF4 in primary common myeloid progenitors (CMPs) or hematopoietic stem cells (HSCs) induced exclusive monocyte differentiation in clonogenic assays, whereas KLF4 deficiency inhibited monocyte but increased granulocyte differentiation. Mechanistic studies demonstrate that KLF4 is a target gene of PU.1. Consistently, KLF4 can rescue PU.1-/- fetal liver cells along the monocytic lineage and can activate the monocytic-specific CD14 promoter. Thus, KLF4 is a critical regulator in the transcriptional network controlling monocyte differentiation.

  • haploinsufficiency of kruppel like factor 4 promotes adenomatous polyposis coli dependent intestinal tumorigenesis
    Cancer Research, 2007
    Co-Authors: Amr M. Ghaleb, Mandayam O Nandan, Jonathan P. Katz, Klaus H Kaestner, Beth B Mcconnell, Vincent W. Yang
    Abstract:

    The zinc finger transcription factor Kruppel-like factor 4 (KLF4) is frequently down-regulated in colorectal cancer. Previous studies showed that the expression of KLF4 was activated by the colorectal cancer tumor suppressor adenomatous polyposis coli (APC) and that KLF4 repressed the Wnt/β-catenin pathway. Here, we examined whether KLF4 plays a role in modulating intestinal tumorigenesis by comparing the tumor burdens in mice heterozygous for the ApcMin allele ( ApcMin/+ ) and those heterozygous for both the ApcMin and KLF4 alleles ( KLF4+/−/ApcMin/+ ). Between 10 and 20 weeks of age, KLF4+/−/ApcMin/+ mice developed, on average, 59% more intestinal adenomas than ApcMin/+ mice ( P < 0.0001). Immunohistochemical staining showed that KLF4 protein levels were lower in the normal-appearing intestinal tissues of KLF4+/−/ApcMin/+ mice compared with wild-type, KLF4+/− , or ApcMin/+ mice. In contrast, the levels of β-catenin and cyclin D1 were higher in the normal-appearing intestinal tissues of KLF4+/−/ApcMin/+ mice compared with the other three genotypes. KLF4 levels were further decreased in adenomas from both ApcMin/+ and KLF4+/−/ApcMin/+ mice compared with their corresponding normal-appearing tissues. Reverse transcription-PCR showed an inverse correlation between adenoma size and KLF4 mRNA levels in both KLF4+/−/ApcMin/+ and ApcMin/+ mice. There was also a progressive loss of heterozygosity of the wild-type Apc allele in adenomas with increasing size from KLF4+/−/ApcMin/+ and ApcMin/+ mice. Results from this study show that KLF4 plays an important role in promoting the development of intestinal adenomas in the presence of ApcMin mutation. [Cancer Res 2007;67(15):7147–54]

  • KLF4 and KLF5 regulate proliferation, apoptosis and invasion in esophageal cancer cells.
    Cancer biology & therapy, 2005
    Co-Authors: Yizeng Yang, Bree G. Goldstein, Hann-hsiang Chao, Jonathan P. Katz
    Abstract:

    KLF4 and KLF5, members of the KLF family of transcription factors, play key roles in proliferation, differentiation, and carcinogenesis in a number of gastrointestinal tissues. While KLF4 is expressed in differentiating epithelial cells, KLF5 is found in proliferating cells of the gastrointestinal tract, including the esophagus. KLF4 regulates a number of genes vital for esophageal epithelial differentiation, and decreased expression of KLF4 is seen in esophageal squamous cancers. Nonetheless, the roles of KLF4 and KLF5 in esophageal tumor progression are not known. Here, using TE2 cells stably infected with retroviral vectors to express KLF4 or KLF5, we demonstrate that KLF4 and KLF5 are key players in a number of cellular processes critical for esophageal carcinogenesis. TE2 cells, derived from a patient with poorly differentiated esophageal squamous cancer, normally lack KLF4 and KLF5. Expression of KLF5 in TE2 cells inhibits proliferation, and both KLF4 and KLF5 decrease viability after treatment with...

  • loss of KLF4 in mice causes altered proliferation and differentiation and precancerous changes in the adult stomach
    Gastroenterology, 2005
    Co-Authors: Jonathan P. Katz, Bree G. Goldstein, Nathalie Perreault, Lori Actman, Sara Mcnally, Debra G Silberg, Emma E Furth, Klaus H Kaestner
    Abstract:

    Background & Aims: The epithelial zinc-finger transcription factor KLF4 (formerly GKLF) regulates cellular proliferation and differentiation in vitro. KLF4 null mice die by postnatal day 1 and show changes in epithelial differentiation of skin and colon. Methods: We used tissuespecific gene ablation to generate mice lacking KLF4 in their gastric epithelia. KLF4 mutant mice and controls were killed for histology, immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR), and serum gastrin levels. KLF4 messenger RNA (mRNA) levels were analyzed in Foxa3-Cdx2 transgenic mice and controls. Human gastric cancers and matched normal tissue were used for qPCR and immunohistochemistry for KLF4. Results: KLF4 mutant mice survive to adulthood and show increased proliferation and altered differentiation of their gastric epithelia. KLF4 mutants also display aberrant expression of acidic mucins and TFF2/SP-positive cells, findings characteristic of premalignant conditions, but no inflammation, intestinal metaplasia, dysplasia, or cancer up to 1 year of age. Expression of KLF4 is nearly absent in human gastric cancer, suggesting that failure to activate KLF4 during normal cellular differentiation may be a common feature of gastric cancers. p21 WAF1/CIP1 is an in vivo target of KLF4, but KLF4 is not a mediator of Cdx2. Conclusions: Loss of a single genetic factor, KLF4, leads to dramatic changes in the gastric epithelia of mice, and KLF4 is part of a regulatory pathway involving p21 WAF1/CIP1 but not Cdx2. Thus, KLF4 is critical for normal gastric epithelial homeostasis.

  • the zinc finger transcription factor KLF4 is required for terminal differentiation of goblet cells in the colon
    Development, 2002
    Co-Authors: Jonathan P. Katz, Vincent W. Yang, Bree G. Goldstein, Nathalie Perreault, Catherine S Lee, Patricia A Labosky, Klaus H Kaestner
    Abstract:

    KLF4 (formerly GKLF) is a zinc-finger transcription factor expressed in the epithelia of the skin, lungs, gastrointestinal tract and several other organs. In vitro studies have suggested that KLF4 plays an important role in cell proliferation and/or differentiation. Mice homozygous for a null mutation in KLF4 die within 15 hours of birth and show selective perturbation of late-stage differentiation structures in the epidermis, but the function of KLF4 in the gastrointestinal tract has not been investigated. To address this issue, we have generated KLF4 –/– mice by homologous recombination in embryonic stem cells. In this study, we provide the first in vivo evidence that KLF4 is a goblet cell-specific differentiation factor in the colon. KLF4 –/– mice exhibit normal cell proliferation and cell death rates in the colon on postnatal day 1. However, KLF4 –/– mice demonstrate a 90% decrease in the number of goblet cells in the colon, show abnormal expression of the goblet cell-specific marker Muc2 by in situ hybridization, have abnormal staining of the colonic epithelium with Alcian Blue for acidic mucins, and lack normal goblet cell morphology by ultrastructural analysis. All other epithelial cell types are present in the colon of KLF4 –/– mice. In summary, KLF4 plays a crucial role in colonic epithelial cell differentiation in vivo.