IKKα Is Required to Maintain Skin Homeostasis and Prevent Skin Cancer

Liu, Bigang; Xia, Xiaojun; Zhu, Feng; Park, Eunmi; Carbajal, Steve; Kiguchi, Kaoru; DiGiovanni, John; Fischer, Susan M.; Hu, Yinling

doi:10.1016/j.ccr.2008.07.017

Cited by 111 publications

(197 citation statements)

References 44 publications

(77 reference statements)

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“…To further verify the effect of IKKa on Mad1 expression in keratinocytes, we re-expressed a series of IKKa doses in keratinocytes lacking the endogenous IKKa isolated from Ikka F/F /K5.Cre mice 15 and found that Mad1 expression was induced by IKKa in a dose-dependent fashion. Filaggrin levels were used as controls for IKKa introduction, 28 because IKKa induces terminal differentiation in keratinocytes (Figure 6c).…”

Section: Resultsmentioning

confidence: 99%

“…15 Previously, we showed that IKKa deletion in the epidermis causes keratinocyte proliferation and reduces cell differentiation through the EGFR/Ras/ ERK pathway. 15 We found that both Tg-4-IKKa and Tg-7-IKKa rescued the epidermal hyperplasia in Tg-4/Ikka F/F /K5.Cre and Tg-7/Ikka F/F /K5.Cre mice, compared with the epidermis of Ikka F/F /K5.Cre mice ( Figure 5). However, some regions were thicker in the Tg-7/Ikka F/F /K5.Cre epidermis than in the Tg-4/Ikka F/F /K5.Cre epidermis.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we detected elevated autocrine activity of EGFR and growth factors through a transcriptional regulation mechanism in IKKa-deficient keratinocytes. 15 Also, it has been reported that IKKa regulates the expression of Max dimer protein 1 (Mad1) and ovo-like 1 (Ovol1), which are differentiation inducers and c-Myc antagonists. 20 Thus, we evaluated whether different levels of transgenic IKKa have different effects on EGFR activity, and on Mad1 and Ovol1 expression levels.…”

Section: Resultsmentioning

confidence: 99%

“…We showed that induced IKKa deletion in keratinocytes causes epidermal hyperplasia and spontaneous skin tumors. 15 We further identified that IKKa loss elevates an excessive autocrine loop of epidermal growth factor receptor (EGFR), Ras, extracellular signal-regulated kinase (ERK), EGFR ligands, and these ligands' activators in the epidermis of both Ikka À/À mice and Ikka F/F /K5.Cre mice, that reintroducing IKKa or inactivating EGFR induces keratinocytes to terminal differentiation, represses epidermal hyperplasia, and prevents skin tumors. Moreover, studies have demonstrated that IKKa upregulates c-Myc antagonists by transforming growth factor-b and Smad pathways in coordinately regulating keratinocyte differentiation and proliferation.…”

mentioning

confidence: 99%

“…It has been shown that the overexpression of IKKa or kinase-inactive IKKa under the control of the keratin (K)-14 promoter or the K5 promoter is able to rescue the skin phenotype of Ikka À/À mice. 14,15 Thus, IKKa is required for embryonic skin development, independent of its kinase activity.…”

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confidence: 99%

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IKKα represses a network of inflammation and proliferation pathways and elevates c-Myc antagonists and differentiation in a dose-dependent manner in the skin

et al. 2011

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Inhibitor of nuclear factor jB kinase-a (IKKa) is required for maintaining skin homeostasis and preventing skin tumorigenesis. However, its signaling has not been extensively investigated. In the present study, we generated two mouse lines that expressed different levels of transgenic IKKa in the basal epidermis under the control of keratin-5 promoter and further evaluated their effects on the major pathways of inflammation, proliferation, and differentiation in the skin. Regardless of the transgenic IKKa levels, the mice develop normally. Because IKKa deletion in keratinocytes blocks terminal differentiation and induces epidermal hyperplasia and skin inflammation, we depleted the endogenous IKKa in these transgenic mice and found that the transgenic IKKa represses epidermal thickness and induces terminal differentiation in a dose-dependent manner. Also, transgenic IKKa was found to elevate expression of Max dimer protein 1 (Mad1) and ovo-like 1, c-Myc antagonists, but repress activities of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), Jun-amino-terminal kinases, c-Jun, signal transducer and activator of transcription 3 (Stat3), and growth factor levels in a dose-dependent fashion in the skin. Moreover, EGFR reduction represses IKKa deletion-induced excessive ERK, Stat3 and c-Jun activities, and skin inflammation. These new findings indicate that elevated IKKa expression not only represses epidermal thickness and induces terminal differentiation, but also suppresses skin inflammation by an integrated loop. Thus, IKKa maintains skin homeostasis through a broad range of signaling pathways.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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IKKα represses a network of inflammation and proliferation pathways and elevates c-Myc antagonists and differentiation in a dose-dependent manner in the skin

et al. 2011

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Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

Zhu

2018

BioEssays

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A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell-mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IkB kinase α (IKKα) is one subunit of the IKK complex required for NF-kB activation. IKK/NF-kB is essential for central tolerance establishment by regulating the development of medullary thymic epithelial cells (mTECs) that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-kB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-kB components, through mTEC (stroma), T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-kB in these diseases.

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Aberrant promoter methylation of multiple genes in malignant ovarian tumors and in ovarian tumors with low malignant potential

Wiley

Katsaros

Chen

et al. 2006

Cancer

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BACKGROUND.Methylation‐mediated suppression of detoxification, DNA repair, and tumor suppressor genes has been implicated in cancer development and progression. Studies also have indicated that concordant methylation of multiple genes (methylator phenotypes), rather than a single gene, may predict cancer prognosis. The current study was designed to determine whether a methylator phenotype exists in ovarian cancer, whether methylation frequencies differ between malignant ovarian tumors and ovarian tumors with low malignant potential (LMP or borderline), and whether methylation of multiple genes affects patient survival.METHODS.The current study included 234 consecutively diagnosed patients with either LMP (n = 19 patients) or malignant (n = 215 patients) ovarian tumors. DNA samples were extracted from fresh frozen tissues and were analyzed for methylation in the promoter region of 6 genes (p16, breast cancer 1 [BRCA1], insulin‐like growth factor‐binding protein 3 [IGFBP‐3], glutathione S‐transferase π 1 [GSTP1], estrogen receptor‐α [ER‐α], and human MutL homologue 1 [hMLH1]) by using methylation‐specific polymerase chain reaction analysis.RESULTS.The frequencies of methylation in malignant tumors and LMP tumors were 0% and 0% for GSTP1, respectively; 9% and 0% for hMLH1, respectively; 21% and 5% for BRCA1, respectively; 42% and 21% for p16, respectively; 44% and 26% for IGFBP‐3, respectively; and 57% and 42% for ER‐α, respectively. A methylator phenotype was not detected, but a calculated methylation index (MI) that was based on the total number of genes methylated in each tumor was associated with ovarian cancer risk and progression. A higher MI was associated with malignant tumors (odds ratio, 10.11; 95% confidence interval [95% CI], 1.19–85.75) and disease progression (hazards ratio, 6.53; 95% CI, 1.39–30.65).CONCLUSIONS.Although a methylator phenotype was not identified, the current results suggested that methylation of multiple genes may play an important role in ovarian cancer development and progression and may have clinical implications in prognosis. Cancer 2006. © 2006 American Cancer Society.

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IKKα Is Required to Maintain Skin Homeostasis and Prevent Skin Cancer

Cited by 111 publications

References 44 publications

IKKα represses a network of inflammation and proliferation pathways and elevates c-Myc antagonists and differentiation in a dose-dependent manner in the skin

IKKα represses a network of inflammation and proliferation pathways and elevates c-Myc antagonists and differentiation in a dose-dependent manner in the skin

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

Aberrant promoter methylation of multiple genes in malignant ovarian tumors and in ovarian tumors with low malignant potential

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