KLF5 governs sphingolipid metabolism and barrier function of the skin
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA710018 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13920269_1.fastq.gz | Fastqsanger.gz | |||
| SRR13920269_2.fastq.gz | Fastqsanger.gz | |||
| SRR13920270_1.fastq.gz | Fastqsanger.gz | |||
| SRR13920270_2.fastq.gz | Fastqsanger.gz | |||
| SRR13920271_1.fastq.gz | Fastqsanger.gz |
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Project description:High-risk B-cell acute lymphoblastic leukemia (B-ALL) remains a therapeutic challenge despite advances in the use of tyrosine kinase inhibitors and chimeric- antigen-receptor engineered T cells. Lymphoblastic-leukemia precursors are highly sensitive to oxidative stress. KLF5 is a member of the Krüppel-like family of transcription factors. KLF5 expression is repressed in B-ALL, including BCR-ABL1+ B-ALL. Here, we demonstrate that forced expression of KLF5 in B-ALL cells bypasses imatinib resistance not associated with mutations of BCR-ABL. Expression of Klf5 impaired leukemogenic activity of BCR-ABL1+ B-cell precursors in vitro and in vivo. The complete genetic loss of Klf5 reduced oxidative stress, increased regeneration of reduced glutathione and decreased apoptosis of leukemic precursors. Klf5 regulation of glutathione levels was mediated by its regulation of glutathione-S-transferase Mu 1 (Gstm1), an important regulator of glutathione-mediated detoxification and protein glutathionylation. Expression of Klf5 or the direct Klf5 target gene Gstm1 inhibited clonogenic activity of Klf5∆/∆ leukemic B-cell precursors and unveiled a Klf5-dependent regulatory loop on glutamine-dependent glutathione metabolism. In summary, we describe a novel mechanism of Klf5 B-ALL suppressor activity through its direct role on the metabolism of antioxidant glutathione levels, a crucial positive regulator of leukemic precursor survival.
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Project description:Sphingolipid metabolism controls mammalian heart regeneration
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Project description:Utilization of lipids as energy substrates after birth causes cardiomyocyte (CM) cell-cycle arrest and loss of regenerative capacity in mammalian hearts. Beyond energy provision, proper management of lipid composition is crucial for cellular and organismal health, but its role in heart regeneration remains unclear. Here, we demonstrate widespread sphingolipid metabolism remodeling in neonatal hearts after injury and find that SphK1 and SphK2, isoenzymes producing the same sphingolipid metabolite sphingosine-1-phosphate (S1P), differently regulate cardiac regeneration. SphK2 is downregulated during heart development and determines CM proliferation via nuclear S1P-dependent modulation of histone acetylation. Reactivation of SphK2 induces adult CM cell-cycle re-entry and cytokinesis, thereby enhancing regeneration. Conversely, SphK1 is upregulated during development and promotes fibrosis through an S1P autocrine mechanism in cardiac fibroblasts. By fine-tuning the activity of each SphK isoform, we develop a therapy that simultaneously promotes myocardial repair and restricts fibrotic scarring to regenerate the infarcted adult hearts.
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Project description:We sequenced mRNA from three independent pairs of mock and c-SRC transformed mouse embryonic fibroblasts and examined changes in expression of sphingolipid metabolism genes Three independent cultures of NIH3T3 MEFs were retrovirally transduced with either pBabe-Puro, og pBabe-Puro containing c-srcY527F. After a 7 day of selection in puromycine the three vector and three src transduced pools were propagated for RNA sequencing.
2013-10-17 | E-GEOD-46340 | biostudies-arrayexpress
Project description:We sequenced mRNA from three independent pairs of mock and c-SRC transformed mouse embryonic fibroblasts and examined changes in expression of sphingolipid metabolism genes
2013-10-17 | GSE46340 | GEO
Project description:We report the effects of dietary n-3 polyunsaturated fatty acids (PUFAs) on sphingolipid metabolism and airway reactivity in the lung. Mice were fed a n3-PUFA enriched fishoil diet or an isocaloric control coconut oil-enriched diet (CO) for 8 weeks. The n-3 PUFA diet affected pulmonary sphingolipid metabolism, and airway reactivity, independent of inflammation or allergic sensitization. These findings support a role for pulmonary sphingolipid homeostasis in asthma and could have implications for the use of n-3 PUFA dietary supplements in asthma.
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Project description:Activation of the Ras/Erk pathway upregulates expression of the Kruppel-like Factor 5 (KLF5) transcription factor, and KLF5 is a downstream mediator of Ras oncogenic signaling. Specifically, in bladder and colon cancer cell lines KLF5 upregulates the Ras-pathway target gene cyclin D1, and facilitates entry into the S phase of the cell cycle. Ras mutations are common in lung cancer, but a role for KLF5 in lung tumorigenesis has not been defined. To this end, we manipulated KLF5 expression in four Ras-mutant human lung adenocarcinoma cell lines to find that KLF5 significantly modulates anchorage-independent growth, a mutant Ras phenotype. However, in a mouse model of human lung adenocarcinoma, K-RasG12D does not critically require Klf5 to mediate oncogenesis or induce cyclin D1 expression. Patients with lung tumors expressing high levels of KLF5 have significantly better prognosis than those with low or no KLF5 expression (opposite of mutant Ras prognosis). The latter may be explained by KLF5 transcriptional repression of the ATP-binding cassette, sub-family G (WHITE), member 2 (ABCG2), an anthracycline transporter. In agreement with this, KLF5 knockdown cells display significantly more Hoechst “side population” and resistance to doxorubicin. In summary, while KLF5 is not an obligate partner in Ras oncogenic signaling, KLF5 control of ABCG2 expression is significant to patient survival.
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Project description:A life-essential function of the epidermis is to provide a physical barrier that prevents the loss of water and electrolytes. Essential mediators of this permeability barrier function include ceramides, cholesterol and very long chain fatty acids. Accordingly, their alteration may lead to distinct human conditions, including psoriasis or atopic dermatitis. Recently, a frameshift mutation in the human ZNF750 gene, that encodes for a zinc finger transcription factor, causing a seborrhea-like dermatitis with psoriasiform element, has brought ZNF750 as a key element for the maintenance of the epidermal tissue homeostasis. To clarify this hypothesis, with its underlying molecular mechanism, we generated a novel mouse knockout by deleting exon 2. Here, we show that genetic deletion of the mouse homolog ZFP750 results in loss of epidermal permeability barrier function. ZFP750-/- mice die shortly after birth, within 12 hours. In the stratum corneum of ZFP750-/- mice levels of ceramides, nonpolar lipids and intercellular lipid lamellae are significantly reduced. The alteration of the epidermal lipid homeostasis is directly linked to the transcriptional activity of ZFP750. Indeed, in addition to epidermal differentiation genes, ZFP750 directly and/or indirectly regulates the expression of nearly 50 crucial enzymes in the biosynthesis of ceramides, such as SPTLC1, DGAT2, SMPD3, ELOVL7 and DEGS2. Overall, our study identifies the transcription factor ZFP750 as a master regulator of lipid biosynthesis and epidermal homeostasis and may contribute to our understanding of the pathogenesis of several human skin diseases.
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