SP and KLF Transcription Factors in Digestive Physiology and Diseases

Kim, Chang-Kyung; He, Ping; Bialkowska, Agnieszka B.; Yang, Vincent W.

doi:10.1053/j.gastro.2017.03.035

Cited by 85 publications

(78 citation statements)

References 302 publications

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“…Our previous studies identified KLF6 as most abundantly expressed in myeloid cells and essential for classic macrophage activation (23). Studies by our group and others have shown that KLF6 contributes to a variety of human inflammatory disease conditions (25,42). Studies by Qi et al (43) implicated role for KLF6 in the early onset of diabetes utilizing rat model system.…”

Section: Discussionmentioning

confidence: 93%

Kruppel‐like factor 6 and miR‐223 signaling axis regulates macrophage‐mediated inflammation

Kim¹,

Ng²,

Patel

et al. 2019

FASEB j.

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Macrophage‐mediated inflammation is an explicitly robust biologic response that plays a critical role in maintaining tissue homeostasis by eliminating deleterious agents. These tissue macrophages tailor appropriate responses to external cues by altering inflammatory gene expression. Therefore, transcription factors and regulators that modulate inflammatory gene expression play an essential role in shaping the macrophage inflammatory response. Here, we identify that Kruppel‐like factor (KLF)6 promotes inflammation by restraining microRNA‐223 (miR‐223) expression in macrophages. We uncovered that pro‐ and anti‐inflammatory agents oppositely regulate KLF6 and miR‐223 expression in macrophages. Using complementary gain‐ and loss‐of‐function studies, we observed that overexpression of KLF6 attenuates and deficiency of KLF6 elevates miR‐223 expression in macrophages. Furthermore, heightened miR‐223 expression in KLF6‐deficient macrophages significantly attenuates inducible proinflammatory gene expression. Concordantly, myeloid‐KZ/6 deficiency significantly curbs diet‐induced adipose tissue inflammation, obesity, glucose intolerance, and insulin resistance. At the molecular level, KLF6 directly represses miR‐223 expression by occupying its promoter region. More importantly, genetic inhibition of miR‐223‐3P in KLF6‐deficient macrophages completely reversed attenuated proinflammatory gene expression in macrophages. Collectively, our studies reveal that KLF6 promotes proinflammatory gene expression and functions by repressing miR‐223 expression in macrophages.—Kim, G.‐D., Ng, H. P., Patel, N., Mahabeleshwar, G. H. Kruppel‐like factor 6 and miR‐223 signaling axis regulates macrophage‐mediated inflammation. FASEB J. 33, 10902–10915 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 93%

Kruppel‐like factor 6 and miR‐223 signaling axis regulates macrophage‐mediated inflammation

Kim¹,

Ng²,

Patel

et al. 2019

FASEB j.

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“…Krüppel-like zinc-finger transcription factor (TF) KLF5 is expressed in both ISCs and transit-amplifying (TA) [13][14][15] cells and regulates epithelial proliferation, differentiation, and development. 13,16 Conditional Klf5 deletion from the entire mouse intestinal epithelium, using Villin-Cre as a driver, impairs epithelial cell proliferation.…”

mentioning

confidence: 99%

Krüppel-like Factor 5 Regulates Stemness, Lineage Specification, and Regeneration of Intestinal Epithelial Stem Cells

Kim

Saxena

Maharjan

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Lgr5 þ ISCs lacking KLF5 proliferate faster than control ISCs but fail to self-renew, resulting in a depleted ISC compartment. Transcriptome analysis revealed that Klf5-null Lgr5 þ cells lose ISC identity and prematurely differentiate. Following irradiation injury, which depletes Lgr5 þ ISCs, reserve Klf5-null progenitor cells fail to dedifferentiate and regenerate the epithelium. Absence of KLF5 inactivates numerous selected enhancer elements and direct transcriptional targets including canonical WNT-and NOTCHresponsive genes. Analysis of human intestinal tissues showed increased levels of KLF5 in the regenerating epithelium as compared to those of healthy controls. CONCLUSION: We conclude that ISC self-renewal, lineage specification, and precursor dedifferentiation require KLF5, by its ability to regulate epigenetic and transcriptional activities of ISC-specific gene sets. These findings have the potential for modulating ISC functions by targeting KLF5 in the intestinal epithelium.

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“…Previous studies showed that Sp4 is overexpressed in pancreatic, bladder, esophageal, breast, prostate, lung, colon, epidermal, thyroid, and rhabdomyosarcoma cancer cell lines and multiple myeloma cell lines, and KD of Sp4 significantly decreases cell growth and migration and induces apoptosis in nine cancer cell lines derived from six different tumors, [ 18,19 ] suggesting that Sp4 is a pro‐oncogene. However, the different Sp4 splicing variants were not considered in these studies; only L‐Sp4 splicing variants were considered.…”

Section: Discussionmentioning

confidence: 99%

Small Protein Hidden in lncRNA LOC90024 Promotes “Cancerous” RNA Splicing and Tumorigenesis

Meng

Chen

et al. 2020

Advanced Science

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Conventional therapies for late‐stage colorectal cancer (CRC) have limited effects because of chemoresistance, recurrence, and metastasis. The “hidden” proteins/peptides encoded by long noncoding RNAs (lncRNAs) may be a novel resource bank for therapeutic options for patients with cancer. Here, lncRNA LOC90024 is discovered to encode a small 130‐amino acid protein that interacts with several splicing regulators, such as serine‐ and arginine‐rich splicing factor 3 (SRSF3), to regulate mRNA splicing, and the protein thus is named “Splicing Regulatory Small Protein” (SRSP). SRSP, but not LOC90024 lncRNA itself, promotes CRC tumorigenesis and progression, while silencing of SRSP suppresses CRC tumorigenesis. Mechanistically, SRSP increases the binding of SRSF3 to exon 3 of transcription factor Sp4, resulting in the inclusion of Sp4 exon 3 to induce the formation of the “cancerous” long Sp4 isoform (L‐Sp4 protein) and inhibit the formation of the “noncancerous” short Sp4 isoform (S‐Sp4 peptide), which lacks the transactivation domain. The upregulated SRSP level is positively associated with malignant phenotypes and poor prognosis in patients with CRC. Collectively, the findings uncover that a lncRNA‐encoded small protein SRSP induces “cancerous” Sp4 splicing variant formation and may be a potential prognostic biomarker and therapeutic target for patients with CRC.

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SP and KLF Transcription Factors in Digestive Physiology and Diseases

Cited by 85 publications

References 302 publications

Kruppel‐like factor 6 and miR‐223 signaling axis regulates macrophage‐mediated inflammation

Kruppel‐like factor 6 and miR‐223 signaling axis regulates macrophage‐mediated inflammation

Krüppel-like Factor 5 Regulates Stemness, Lineage Specification, and Regeneration of Intestinal Epithelial Stem Cells

Small Protein Hidden in lncRNA LOC90024 Promotes “Cancerous” RNA Splicing and Tumorigenesis

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