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Gene expression alteration by macrophage depletion in IKKα mutant mice

ABSTRACT: We generated Ikkα-KA/KA knock-in mice (KA/KA), in which an ATP binding site of Ikkα Lys 44 was replaced by alanine. The knock-in mice develop severe skin lesions and begin to die after 6 to 10 months. We also found lung SCCs in some of the mice. To study lung SCC development, we stabilize the skin condition by crossing KA/KA with Lori.Ikkα transgenic mice to generate KA/KA-Lori.Ikkα mice, which 100% spontaneously developed lethal lung SCC at 4 to 6 months of age. Clodronate-liposomes obtained from Dr. N. van Rooijen (Vrije Universiteit, Amsterdam, Netherlands) were intravenously injected into mice twice every week, started in 4 weeks old mice, and continued for 3 months. The dose of clodronate-liposomes was 100µl during the first month and elevated to 150 100µl after that. The depletion efficacy was confirmed by detecting pulmonary macrophages with Flow Cytometry. Depletion of macrophages in these KA/KA-Lori.Ikkα mice could significantly reduce inflammation and prevent lung SCC developmrnt. This aim of this microarray assay is to identify differentially expressed genes among Wild type, KA/KA-Lori.Ikkα, and macophage-depleted KA/KA-Lori.Ikkα mice, which may highlight the important genes or parthways involved in inflammation-associated lung SCC carcinogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE37655 | GEO | 2012/05/01

SECONDARY ACCESSION(S): PRJNA162673

REPOSITORIES: GEO

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Gene expression alteration by macrophage depletion in IKKα mutant mice

Project description:We generated Ikkα-KA/KA knock-in mice (KA/KA), in which an ATP binding site of Ikkα Lys 44 was replaced by alanine. The knock-in mice develop severe skin lesions and begin to die after 6 to 10 months. We also found lung SCCs in some of the mice. To study lung SCC development, we stabilize the skin condition by crossing KA/KA with Lori.Ikkα transgenic mice to generate KA/KA-Lori.Ikkα mice, which 100% spontaneously developed lethal lung SCC at 4 to 6 months of age. Clodronate-liposomes obtained from Dr. N. van Rooijen (Vrije Universiteit, Amsterdam, Netherlands) were intravenously injected into mice twice every week, started in 4 weeks old mice, and continued for 3 months. The dose of clodronate-liposomes was 100µl during the first month and elevated to 150 100µl after that. The depletion efficacy was confirmed by detecting pulmonary macrophages with Flow Cytometry. Depletion of macrophages in these KA/KA-Lori.Ikkα mice could significantly reduce inflammation and prevent lung SCC developmrnt. This aim of this microarray assay is to identify differentially expressed genes among Wild type, KA/KA-Lori.Ikkα, and macophage-depleted KA/KA-Lori.Ikkα mice, which may highlight the important genes or parthways involved in inflammation-associated lung SCC carcinogenesis. Three samples were analyzed: 1. WT (lung tissue from wild type mouse); 2. KA2 (mixture tissue of lung SCC and tumor neighbor from KA/KA-Lori-Ikkα mouse ); 3. KAT (lung tissue from KA/KA-Lori-Ikkα mouse with macrophage depletion treatment)

2012-04-30 | E-GEOD-37655 | biostudies-arrayexpress

Gene expression alteration by different cell lines derived from lung SCC of IKKα mutant mice

Project description:In this study, we found that kinase-dead IKKα knockin (KAL) mice. develop spontaneous lung squamous cell carcinomas (SCCs) associated with IKKα downregulation and marked pulmonary inflammation.KKα downregulation dysregulates the expression of multiple oncogenes and tumor suppressors in K5+ lung epithelial cells. The mutant macrophages increase inflammatory responses and oxidative stress to promote DNA damage in IKKα-mutant K5+ lung epithelial cells, which further dysregulate the levels of multiple oncogenes, tumor suppressors, and stem cell genes, thereby promoting the IKKαlowK5+p63hi cell transition to tumor cells in L-IkkαKA/KA lungs. To further investigate the underlying mechanisms by which the lung SCC development, we generated two cell lines, named as S1 and S2 individually, which were derived from KAL lung SCC. The S1 cells express high level of Sca1 and exhibit tumorigenic phenotype, while the S2 cells express low level of Sca1 and exhibit less tumorigenic phenotype. The aim of this microarray assay is to identify differentially expressed genes between S1 and S2 cells, which may highlight the important genes or pathways involved in inflammation-associated lung SCC carcinogenesis.

2015-01-27 | GSE65291 | GEO

IKKα promotes intestinal tumorigenesis

Project description:Depending on the tumor type IκB kinase α (IKKα) can act as tumor promoter or tumor suppressor in various malignancies. Here we demonstrate a key function of IKKα in the suppression of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of IFNγ expressing M1-like myeloid cells. In IKKα mutant mice M1-like polarization is not controlled in a cell autonomous manner but depends rather on the interplay of both IKKα mutant tumor epithelia and immune cells. Tamoxifen-inducible β-catc.a. mice comprise an excellent model to study Wnt-dependent tumor initiation. These mice are characterized by IEC-restricted stabilization of β-catenin causing rapid expansion of intestinal crypts and loss of differentiated IEC. To further explore the underlying IKKα controlled pro-proliferative mechanism, we performed a microarray analysis comparing RNA isolated from wildtype, IkkαAA/AA, β-catc.a. or β-catc.a./IkkαAA/AA IEC 15 days after the first tamoxifen administration. and within 4 weeks β-catc.a. mice succumb to this marked crypt hyperproliferation

2014-06-01 | E-GEOD-51631 | biostudies-arrayexpress

IKKα promotes intestinal tumorigenesis

2014-06-01 | GSE51631 | GEO

Comparing RNA expression profiles of KALori and KANSL mouse lungs

Project description:We have reported that pulmonary infiltrating macrophages, which highly express inducible nitric-oxide synthase (iNOS/NOS2), play a critical role for driving spontaneous lung SCC development in a new mouse model (L-Ikka KA/KA; KA/KA) that mimics human lung SCC development. However, the role of NOS2 in lung SCC development is unknown. Our data suggests deletion of the gene iNOS prevents tumorogenesis in this mouse model. We use microarray data to compare levels of expression of genes associated with lung tumor development and prevention.

2017-07-22 | GSE101759 | GEO

IKKα signaling in the nucleus or cytoplasm of keratinocytes leads to opposite skin phenotypes.

Project description:The skin exerts essential roles for the organism survival, such as environmental barrier and immune functions. IKKα is known as an essential protein for skin homeostasis. However, the functions performed by IKKα in the skin and the mechanisms it employs are largely unknown, leading to contradictory interpretations and results regarding the consequences of its deregulation in pathologies such as non-melanoma skin cancer (NMSC). Here, using our previously generated transgenic mouse models which express IKKα in the cytoplasm (C-IKKα mice) or in the nucleus (N-IKKα mice) of basal keratinocytes, we demonstrate that at each subcellular localization, IKKα distinctly regulates signaling pathways important for maintaining the balance between keratinocyte proliferation and differentiation, as well as the inflammatory response of the skin. As a result, N-IKKα mice show an atrophic epidermis with exacerbated terminal differentiation, reminiscent of alterations observed in patients with ichthyosis. Conversely, C-IKKα mice display a hyperplastic epidermis with impaired epidermal differentiation and pustular inflammation, resembling patients with pustular psoriasis. Interestingly, C-IKKα keratinocytes are almost devoid of nuclear IKKα due to endogenous IKKα downregulation. However, these changes in the skin of C-IKKα mice do not lead to the development of squamous cell carcinomas (SCCs), unlike N-IKKα mice, which develop spontaneous SCCs.

2024-11-14 | GSE239533 | GEO

IKKα Is Required to Maintain Skin Homeostasis and Prevent Skin Cancer

Project description:It has long been known that excessive mitotic activity due to H-Ras can block keratinocyte differentiation and cause skin cancer. It is not clear, however, whether there are any innate surveillants that ensure keratinocytes undergoing terminal differentiation, preventing the disease. IKKα induces keratinocyte terminal differentiation and its reduction promotes skin tumor development. However, its nature function in skin cancer is unknown. Here we found that mice with IKKα deletion in keratinocytes or in hair follicle keratinocytes developed a thickened epidermis and spontaneous squamous cell-like carcinomas. Inactivation of epidermal growth factor receptor (EGFR) or reintroduction of IKKα inhibited excessive mitosis, induced terminal differentiation, and prevented skin cancer through an EGFR-driven autocrine loop in mice. Thus, IKKα serves as an innate surveillant.

2009-07-14 | GSE12111 | GEO

Compound heterozygous mutations in the kinase domain of IKKα lead to immunodeficiency and immune dysregulation

Project description:IKKα, encoded by CHUK, is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKβ. Absence of IKKα cause fetal encasement syndrome in human, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and cause combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features. We showed that both variants were kinase dead mutants. Non-canonical NF-κB activation was abolished in stromal and immune cells while the canonical pathway was partially impaired. Reintroducing wild-type CHUK restored non-canonical NF-κB activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies. Thus, this is the first case of bi-allelic CHUK mutations disrupting IKKα kinase function, broadening non-canonical NF-κB defect understanding and suggesting IKKα's role in both NF-κB pathways.

2024-11-24 | GSE267600 | GEO

Microglial activation protects from vascular degeneration in a rat model of inflammatory retinal vasoregression.

Project description:Microglial activation represents a hallmark of inflammatory retinal diseases like diabetic retinopathy. Anti-inflammatory and especially microglia modulating approaches have been proposed as therapies for these diseases. In this study, clodronate-coated liposomes were intravitreally injected to investigate the effects of increased microglial activation on vasoregression in a model of retinal degeneration. Clodronate-coated liposomes, injected twice over a period of 5 weeks to study the effects of long term clodronate treatment on microglial activation, vasoregression (acellular capillary formation and pericyte loss) and to identify the pathways mediating the observed effects.

2021-01-29 | GSE165743 | GEO

Regulation of epidermal differentiation through KDF1-mediated deubiquitination of IKKα

Project description:Progenitor cells at the basal layer of skin epidermis play an essential role in maintaining tissue homeostasis and enhancing wound repair in skin. The proliferation, differentiation, and cell death of epidermal progenitor cells have to be delicately regulated, as deregulation of this process can lead to many skin diseases, including skin cancers. However, the underlying molecular mechanisms involved in skin homeostasis remain poorly defined. In this study, with quantitative proteomics approach, we identified an important interaction between KDF1 (Keratinocyte Differentiation Factor 1) and IKKα (IκB kinase α) in differentiating skin keratinocytes. Ablation of either KDF1 or IKKα in mice leads to similar but striking abnormalities in skin development, particularly in skin epidermal differentiation. With biochemical and mouse genetics approach, we further demonstrate that the interaction of IKKα and KDF1 is essential for epidermal differentiation. To probe deeper into the mechanisms, we find that KDF1 associates with a deubiquitinating protease, USP7 (Ubiquitin Specific Peptidase 7), and KDF1 can regulate skin differentiation through deubiquitination and stabilization of IKKα. Taken together, our study unravels an important molecular mechanism underlying skin tissue homeostasis and epidermal differentiation.

2020-05-13 | PXD015673 | Pride

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