Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both the diversity and the precisely regulated tissue- and differentiation-specific expression patterns of keratins suggest that these proteins have specific functions in epithelia besides their well known maintenance of cell integrity. In the search for these specific functions, our previous results have demonstrated that the expression of K10, a keratin expressed in postmitotic suprabasal cells of the epidermis, prevents cell proliferation through the inhibition of Akt kinase activity. Given the roles of Akt in NF-kappa B signaling and the importance of these processes in the epidermis, a study was made into the possible alterations of the NF-kappa B pathway in transgenic mice expressing K10 in the proliferative basal layer. It was found that the inhibition of Akt, mediated by K10 expression, leads to impaired NF-kappa B activity. This appears to occur through the decreased expression of IKK beta and IKK gamma. Remarkably, increased production of tumor necrosis factor alpha and concomitant JNK activation was observed in the epidermis of these transgenic mice. These results confirm that keratin K10 functions in vivo include the control of many aspects of epithelial physiology, which affect the cells not only in a cell autonomous manner but also influence tissue homeostasis.
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PMID:Impaired NF-kappa B activation and increased production of tumor necrosis factor alpha in transgenic mice expressing keratin K10 in the basal layer of the epidermis. 1256 51

This study describes the development of a novel thiocationic (OBEHYTOP) lipid-based formulation of phosphorothioate antisense oligonucleotides (PAOs) showing inhibitory activity against mycobacterium tuberculosis (mTB) as measured by an in vitro BACTEC 460TB assay. PAOs were designed based on sequences complementary to essential regions of the mycobacterial genome from published nucleic acid databases in GenBank. These included the superoxide dismutase sod A gene (TBS3), catalase-peroxidase katG gene (TBK1, TBK10), RNA polymerase beta-subunit rpo B gene (TBR5) and diaminopimelate decarboxylase lys A gene (TBL5). The effect of PAOs (TBS3, K1, K10, R5 and L5) alone on mTB was not significant compared with the no-drug control over a period of exposure of 150 h (ranges of -11.8 to +23.58% at 72 h; 15.26 to +25.82% at 96 h and -5.51 to +24.00% at 150 h). Liposomal formulations (10:5:2 OBEHYTOP:oleic acid:vitamin D3) of PAOs resulted in statistically significant (p < 0.05 in all cases) inhibition (ranges of -51.45 to -63.00% at 72 h; -56.75 to -67.96% at 96 h; -51.45 to -60.26% at 150 h) compared with PAOs alone, thiocationic liposomal control and liposomal components. Positive controls of streptomycin and isoniazid used at their minimum inhibitory concentrations of 2.00 and 0.10 microM, respectively, resulted in average % inhibition values of -94% and -97.36%, respectively, indicating that these thiocationic lipid-formulated PAOs showed inhibitory activity directed against mTB in vitro.
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PMID:A novel thiocationic liposomal formulation of antisense oligonucleotides with activity against Mycobacterium tuberculosis. 1275 11

Nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays an important role in the immune system and cell death. Many viral proteins modulate NF-kappaB to escape host immune surveillance, promote cell survival, and enhance viral replication. In the present study, we show that NF-kappaB activity is downmodulated by viral interferon regulatory factor 3 (vIRF3), which is encoded by Kaposi's sarcoma-associated herpesvirus open-reading frame K10.5. vIRF3 repressed NF-kappaB-dependent transcription in a dose-dependent manner and inhibited the activation of NF-kappaB induced by tumor necrosis factor (TNF)-alpha. In vivo studies showed vIRF3 inhibited IkappaB kinase beta (IKKbeta) activity, but not IKKalpha activity, resulting in reduced IkappaB phosphorylation. Immunofluorescence assays showed that vIRF3 interfered with nuclear translocation of NF-kappaB. In addition, consistent with the inhibition of NF-kappaB activity, vIRF3 sensitized cells to TNF-alpha-induced apoptosis. While vIRF3 interacts with IKKbeta in vitro and in 293T cells, we were unable to demonstrate vIRF3-IKKbeta interaction in BCBL-1 cells. Our results indicate that vIRF3 can regulate the host immune system and apoptosis via inhibition of NF-kappaB activity.
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PMID:Inhibition of nuclear factor kappaB activity by viral interferon regulatory factor 3 of Kaposi's sarcoma-associated herpesvirus. 1520 54

Squamous cell carcinomas (SCCs) of the skin display different clinical features according to their epithelial differentiation grade and histological variant. Understanding the causes of these divergences might increase the curability of SCCs. Therefore, it is important to study the mechanisms of differentiation in keratinocytes. IKK (IkappaB kinase) alpha is an important protein for epidermal morphogenesis, although the pathways through which it exerts its function are unknown and controversy exists about its role in cancer development. We show that enhanced IKKalpha expression increases both early and terminal differentiation of human keratinocytes through an E-cadherin-dependent mechanism. Increased expression of IKKalpha in mouse tumorigenic epidermal cells leads to changes in the differentiation pattern of the resulting SCCs, originating a distinct histological variant that resembles the human acantholytic SCC (ASCC) variant. Although human ASCCs have an aggressive clinical course and high risk of metastasis, nothing is known about their etiology. We show that human ASCCs, as observed in the counterpart IKKalpha murine tumors, express high levels of both IKKalpha and E-cadherin, with absence of keratins K1 and K10, usually co-expressed with IKKalpha and E-cadherin. The tight correlation between the properties of both murine and human ASCC variants strongly suggests that IKKalpha is responsible for the development of this human SCC variant.
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PMID:IKKalpha enhances human keratinocyte differentiation and determines the histological variant of epidermal squamous cell carcinomas. 1860 71