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IKK?/NF?Bp65 activated by interleukin-13 targets the autophagy-related genes LC3B and beclin 1 in fibroblasts co-cultured with breast cancer cells.

ABSTRACT: Interleukin-13 (IL-13), a Th2 cytokine, plays an important role in fibrosis, inflammation, tissue hyperresponsiveness and tumor development. Although studies have demonstrated that IL-13 exerts its roles through signal transducer and activator of transcription 6 (STAT6) signaling pathway, recent studies have revealed that I kappa B kinase (IKK)/nuclear factor kappa B (NF?B) pathway may also be involved in. The aim of this study was to investigate whether IL-13 delivers signals to IKK?/NF?Bp65 and whether autophagy genes are IL-13-induced the activation of NF?Bp65 transcriptional targets in fibroblasts of breast tumor stroma. We examined the phosphorylation of IKK?, the activation of NF?Bp65 and NF?Bp65-targeted autophagy genes in fibroblasts co-cultured with breast cancer cells under the condition of IL-13 stimulation. Results of this study showed that IL-13 induced IKK? phosphorylation in the fibroblast line ESF co-cultured with breast cancer cell line BT474, and subsequently NF?Bp65 was activated and aimed at beclin 1 and microtubule-associated protein 1 light chain 3 B (MAP1LC3B or LC3B) in these ESF cells. BMS345541, an inhibitor of IKK/NF?B pathway, significantly inhibited the IL-13-induced the activation of NF?B and also inhibited NF?B-targeted beclin 1 and LC3B expression. Our results suggest that IL-13 regulates beclin 1 and LC3B expression through IKK?/NF?Bp65 in fibroblasts co-cultured with breast cancer cells, and IL-13 plays role in activating IKK?/NF?Bp65.

SUBMITTER: Li WL

PROVIDER: S-EPMC4812107 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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IKKβ/NFκBp65 activated by interleukin-13 targets the autophagy-related genes LC3B and beclin 1 in fibroblasts co-cultured with breast cancer cells.

Li Wen-Lin WL Xiong Li-Xia LX Shi Xiao-Yu XY Xiao Liang L Qi Guan-Yun GY Meng Chuang C

Experimental and therapeutic medicine 20160208 4

Interleukin-13 (IL-13), a Th2 cytokine, plays an important role in fibrosis, inflammation, tissue hyperresponsiveness and tumor development. Although studies have demonstrated that IL-13 exerts its roles through signal transducer and activator of transcription 6 (STAT6) signaling pathway, recent studies have revealed that I kappa B kinase (IKK)/nuclear factor kappa B (NFκB) pathway may also be involved in. The aim of this study was to investigate whether IL-13 delivers signals to IKKβ/NFκBp65 an ...[more]

PMID: 27073433

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Project description:Nine neurodegenerative diseases are caused by expanded polyglutamine (polyQ) tracts in different proteins, such as huntingtin in Huntington's disease and ataxin 3 in spinocerebellar ataxia type 3 (SCA3). Age at onset of disease decreases with increasing polyglutamine length in these proteins and the normal length also varies. PolyQ expansions drive pathogenesis in these diseases, as isolated polyQ tracts are toxic, and an N-terminal huntingtin fragment comprising exon 1, which occurs in vivo as a result of alternative splicing, causes toxicity. Although such mutant proteins are prone to aggregation, toxicity is also associated with soluble forms of the proteins. The function of the polyQ tracts in many normal cytoplasmic proteins is unclear. One such protein is the deubiquitinating enzyme ataxin 3 (refs 7, 8), which is widely expressed in the brain. Here we show that the polyQ domain enables wild-type ataxin 3 to interact with beclin 1, a key initiator of autophagy. This interaction allows the deubiquitinase activity of ataxin 3 to protect beclin 1 from proteasome-mediated degradation and thereby enables autophagy. Starvation-induced autophagy, which is regulated by beclin 1, was particularly inhibited in ataxin-3-depleted human cell lines and mouse primary neurons, and in vivo in mice. This activity of ataxin 3 and its polyQ-mediated interaction with beclin 1 was competed for by other soluble proteins with polyQ tracts in a length-dependent fashion. This competition resulted in impairment of starvation-induced autophagy in cells expressing mutant huntingtin exon 1, and this impairment was recapitulated in the brains of a mouse model of Huntington's disease and in cells from patients. A similar phenomenon was also seen with other polyQ disease proteins, including mutant ataxin 3 itself. Our data thus describe a specific function for a wild-type polyQ tract that is abrogated by a competing longer polyQ mutation in a disease protein, and identify a deleterious function of such mutations distinct from their propensity to aggregate.

Dataset Information

IKK?/NF?Bp65 activated by interleukin-13 targets the autophagy-related genes LC3B and beclin 1 in fibroblasts co-cultured with breast cancer cells.

Publications

IKKβ/NFκBp65 activated by interleukin-13 targets the autophagy-related genes LC3B and beclin 1 in fibroblasts co-cultured with breast cancer cells.

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