Notch Inhibits Expression of the Krüppel-Like Factor 4 Tumor Suppressor in the Intestinal Epithelium

Ghaleb, Amr M.; Aggarwal, Gaurav; Bialkowska, Agnieszka B.; Nandan, Mandayam O.; Yang, Vincent W.

doi:10.1158/1541-7786.mcr-08-0224

Cited by 100 publications

(101 citation statements)

References 49 publications

(97 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because KLF4 has an important role in many biological processes, its expression may be regulated by many different regulators (21,44). Therefore, miR-10b, as one of its post-transcriptional regulators, could partly influence its protein level but may not have a correlation with its expression level.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-10b Promotes Migration and Invasion through KLF4 in Human Esophageal Cancer Cell Lines

Tian

Luo

Cai

et al. 2010

Journal of Biological Chemistry

275

207

View full text Add to dashboard Cite

Recently, microRNAs have emerged as regulators of cancer metastasis through acting on multiple signaling pathways involved in metastasis. In this study, we have analyzed the level of miR-10b and cell motility and invasiveness in several human esophageal squamous cell carcinoma cell lines. Our results reveal a significant correlation of miR-10b level with cell motility and invasiveness. Overexpression of miR-10b in KYSE140 cells increased cell motility and invasiveness, whereas inhibition of miR-10b in EC9706 cells reduced cell invasiveness, although it did not alter cell motility. Additionally, we identified KLF4, a known tumor suppressor gene that has been reported to suppress esophageal cancer cell migration and invasion, as a direct target of miR-10b. MicroRNAs, a class of small noncoding RNAs, have been identified as a new kind of gene expression regulators through targeting mRNAs for translational repression or cleavage (1-3). Lately, emerging evidence suggests important roles for miRNAs 2 in apoptosis (4), hematopoietic development (5), cell proliferation (6), skin morphogenesis (7), and neural development (8). Deregulation of miRNAs has also been reported in a variety of tumors, including breast cancer, leukemia, lung cancer, and colon cancer (9 -11), which indicated a significant correlation between miRNAs and human malignancy. miRNA expression profiling in esophageal cancers revealed a distinct miRNA signature (12, 13), and some miRNAs showed correlation with several clinicopathologic parameters (13). Furthermore, miR-21 is reported to regulate the proliferation and invasion in ESCC (14), and the miR-106b-25 polycistron is activated by genomic amplification and is potentially involved in esophageal neoplastic progression (15), providing evidence of a causal role for miRNAs in esophageal cancer development.Recent studies show that miRNAs may act as activators or inhibitors of tumor metastasis by acting on multiple signaling pathways involved in metastasis (16 -18). Ma et al. (16) found that miR-10b initiates invasion and metastasis in breast cancer. miR10b, induced by the prometastatic transcription factor TWIST1, proceeds to inhibit translation of mRNA of HOXD10, a transcription factor already known for its roles in cell motility (19), resulting in increased expression of a pro-metastatic gene, RHOC. This study has provided the first evidence for a role of miRNA in tumor metastasis. Subsequently several additional miRNAs have been reported to act on various steps of metastasis (17, 18).Krüppel-like factor 4 (KLF4), a zinc finger protein of the Krüp-pel-like factor family, plays a role in cell cycle regulation, differentiation, and rises in response to DNA damage, serum starvation, and contact inhibition (20, 21). In line with these studies, the loss of KLF4 expression has been reported in several human tumors, including colorectal, stomach, esophageal, and bladder cancers (22-25), which indicates its tumor suppressor role. However, KLF4 also exhibits oncogenic properties. Overexpression of KLF4 could b...

show abstract

Section: Discussionmentioning

confidence: 99%

MicroRNA-10b Promotes Migration and Invasion through KLF4 in Human Esophageal Cancer Cell Lines

Tian

Luo

Cai

et al. 2010

Journal of Biological Chemistry

275

207

View full text Add to dashboard Cite

show abstract

“…The incompetence of DN2 cells leads to a block at the DN2-to-DN3 transition in Klf4Tg mice. In humans, NOTCH signaling downregulates KLF4 expression in the gut [30][31]. Interestingly, Notch signaling is also a positive regulator of T cell lineage and Notch ligands are found on stromal cells throughout the thymus [5,32].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells

et al. 2011

View full text Add to dashboard Cite

The roles of the reprogramming factors Oct4, Sox2, c-Myc and Klf4 in early T cell development are incompletely defined. Here, we show that Klf4 is the only reprogramming factor whose expression is downregulated when early thymic progenitors (ETPs) differentiate into T cells. Enforced expression of Klf4 in uncommitted progenitors severely impaired T cell development mainly at the DN2-to-DN3 transition when T cell lineage commitment occurs and affected the transcription of a variety of genes with crucial functions in early T cell development, including genes involved in microenvironmental signaling (IL-7Rα), Notch target genes (Deltex1), and essential T cell lineage regulatory or inhibitory genes (Bcl11a, SpiB, and Id1). The survival of thymocytes and the rearrangement at the Tcrb locus were impaired in the presence of enforced Klf4 expression. The defects in the DN1-to-DN2 and DN2-to-DN3 transitions in Klf4 transgenic mice could not be rescued by the introduction of a TCR transgene, but was partially rescued by restoring the expression of IL-7Rα. Thus, our data indicate that the downregulation of Klf4 is a prerequisite for T cell lineage commitment.

show abstract

“…The interaction between Notch receptors and their ligands (Jagged 1 and 2 and Delta-like 1, 3 and 4) results in proteolytic cleavage of Notch by a γ-secretase, which releases the Notch intracellular domain (NICD) from the plasma membrane, initiating a subsequent nuclear forms a complex with one of three transcriptional regulators, including CSL [collectively referring to C-promoter binding factor (CBF)-1, Suppressor of Hairless in Drosophila, and Lag-1 in Caenorhabditis elegans also known as recombination signal-binding protein Jκ(RBP-Jκ)], mastermind (MAML)-1 and p300/CBP, followed by transcriptional activation of a set of target genes, including the hairy enhancer-of-split (Hes) gene family (Iso et al, 2003;Katoh and Katoh, 2007). Since Hes-1 is a transcriptional repressor, Notch signaling negatively regulates the Krüppel-like factor 4 (KLF4) through its activation of Hes-1 expression (Ghaleb et al, 2008). KLF4 is highly expressed in terminally differentiated epithelial cells in the colon (Shields et al, 1996) and is also believed to be a tumor suppressor gene (Abbas and Dutta, 2009).…”

Section: Notch Signaling and Colon Cancermentioning

confidence: 99%

“…It was also reported that the activation of Notch signaling is essential for the development of adenomas in APC Min/+ mice (van Es et al, 2005) and self-renewal of tumor-initiating cells (Sikandar et al, 2010). Importantly, Hes1 is known to suppress the expression of Krüppel-like factor 4 (KLF4), a transcriptional repressor (Ghaleb et al, 2008). KLF4 is a zinc finger-containing transcription factor that is highly expressed in terminally differentiated epithelial cells of the intestine (Shields et al, 1996;Dang et al, 2000).…”

Section: Notch Signaling and Colon Cancermentioning

confidence: 99%

Dietary Non-nutritive Factors in Targeting of Regulatory Molecules in Colorectal Cancer: An Update

Pandurangan

Esa²

2013

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Colorectal cancer (CRC), a complex multi-step process involving progressive disruption of homeostatic mechanisms controlling intestinal epithelial proliferation/inflammation, differentiation, and programmed cell death, is the third most common malignant neoplasm worldwide. A number of promising targets such as inducible nitric acid (iNOS), cyclooxygenase (COX)-2, NF-E2-related factor 2 (Nrf2), Wnt/β-catenin, Notch and apoptotic signaling have been identified by researchers as useful targets to prevent or therapeutically inhibit colon cancer development. In this review article, we aimed to explore the current targets available to eliminate colon cancer with an update of dietary and non-nutritional compounds that could be of potential use for interaction with regulatory molecules to prevent CRC.

show abstract

Notch Inhibits Expression of the Krüppel-Like Factor 4 Tumor Suppressor in the Intestinal Epithelium

Abstract: The zinc finger-containing transcription factor, Krü ppel-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 Apc Min/+ mice promotes intestinal tumorigenesis.

Cited by 100 publications

References 49 publications

MicroRNA-10b Promotes Migration and Invasion through KLF4 in Human Esophageal Cancer Cell Lines

MicroRNA-10b Promotes Migration and Invasion through KLF4 in Human Esophageal Cancer Cell Lines

Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells

Dietary Non-nutritive Factors in Targeting of Regulatory Molecules in Colorectal Cancer: An Update

Contact Info

Product

Resources

About