The aryl hydrocarbon receptor nuclear translocator (ARNT) is involved in xenobiotic and hypoxic responses, and we previously showed that ARNT also regulates nuclear factor-κB (NF-κB) signaling by altering the DNA binding activity of the RelB subunit. However, our initial study of ARNT-mediated RelB modulation was based on simultaneous suppression of the two ARNT isoforms, isoform 1 and 3, and precluded the examination of their individual functions. We find here that while normal lymphocytes harbor equal levels of isoform 1 and 3, lymphoid malignancies exhibit a shift to higher levels of ARNT isoform 1. These elevated levels of ARNT isoform 1 are critical to the proliferation of these cancerous cells, as suppression of isoform 1 in a human multiple myeloma (MM) cell line, and an anaplastic large cell lymphoma (ALCL) cell line, triggered S-phase cell cycle arrest, spontaneous apoptosis, and sensitized cells to doxorubicin treatment. Furthermore, co-suppression of RelB or p53 with ARNT isoform 1 prevented cell cycle arrest and blocked doxorubicin induced apoptosis. Together our findings reveal that certain blood cancers rely on ARNT isoform 1 to potentiate proliferation by antagonizing RelB and p53-dependent cell cycle arrest and apoptosis. Significantly, our results identify ARNT isoform 1 as a potential target for anticancer therapies.
T cells devoid of tumor necrosis factor receptor associated factor-3 (Traf3) exhibit decreased proliferation, sensitivity to apoptosis, and an improper response to antigen challenge. We therefore hypothesized that TRAF3 is critical to the growth of malignant T cells. By suppressing TRAF3 protein in different cancerous T cells, we found that anaplastic large cell lymphoma (ALCL) cells require TRAF3 for proliferation. Since reducing TRAF3 results in aberrant activation of the noncanonical nuclear factor-κB (NF-κB) pathway, we prevented noncanonical NF-κB signaling by suppressing RelB together with TRAF3. This revealed that TRAF3 regulates proliferation independent of the noncanonical NF-κB pathway. However, suppression of NF-κB-inducing kinase (NIK) along with TRAF3 showed that high levels of NIK have a partial role in blocking cell cycle progression. Further investigation into the mechanism by which TRAF3 regulates cell division demonstrated that TRAF3 is essential for continued PI3K/AKT and JAK/STAT signaling. In addition, we found that while NIK is dispensable for controlling JAK/STAT activity, NIK is critical to regulating the PI3K/AKT pathway. Analysis of the phosphatase and tensin homolog (PTEN) showed that NIK modulates PI3K/AKT signaling by altering the localization of PTEN. Together our findings implicate TRAF3 as a positive regulator of the PI3K/AKT and JAK/STAT pathways and reveal a novel function for NIK in controlling PI3K/AKT activity. These results provide further insight into the role of TRAF3 and NIK in T cell malignancies and indicate that TRAF3 differentially governs the growth of B and T cell cancers.
2 Summary (max 150 words)Skeletal muscle mitochondrial fatty acid (FA) overload in response to chronic overnutrition is a 1 prominent pathophysiological mechanism in obesity-induced metabolic disease. Increased 2 disposal of FAs is therefore an attractive strategy for intervening in obesity and related disorders.3 Skeletal muscle uncoupling protein 3 (UCP3) activity is associated with increased FA oxidation 4 and antagonizes weight gain in mice on obesogenic diets, but the mechanisms involved are not 5 clear. Here, we show that UCP3 forms a direct, FA-stimulated, mitochondrial matrix-localized 6 complex with the auxiliary unsaturated FA-metabolizing enzyme, Δ 3,5-Δ 2,4 dienoyl-CoA-isomerase 7 (ECH1). Expression studies in C2C12 myoblasts that functionally augments state 4 (uncoupled) 8 respiration and FA oxidation in skeletal myocytes. 10Mechanistic studies indicate that ECH1:UCP3 complex formation is likely stimulated by FA 11 import into the mitochondria to enhance uncoupled respiration and unsaturated FA oxidation in 12 mouse skeletal myocytes. In order to characterize the contribution of ECH1-dependent FA 13 metabolism in NST, we generated an ECH1 knockout mouse and found that these mice were 14 severely cold intolerant, despite an up-regulation of UCP3 expression in SKM. These findings 15 illuminate a novel mechanism that links unsaturated FA metabolism with mitochondrial 16 uncoupling and non-shivering thermogenesis in SKM. 17 18 Abbreviations used: Uncoupling proteins (UCP); Uncoupling protein 3 (UCP3); Skeletal Muscle 19 (SKM); non-shivering thermogenesis (NST); Fatty acid (FA); ∆ 3,5 ∆ 2,4 dienoyl-CoA isomerase 20 (ECH1) BAT, HD, ANT, TM, MTS, DIG, MAT, IMS, OMM 21 ECH1 (Ren et al. 2004). Additionally, FA levels are significantly elevated following ECH1-1 knockdown in C. elegans compared to wild type, suggesting that normal b-oxidation is 2 compromised in this model. Furthermore, mice lacking dienoyl-CoA reductase, an enzyme that 3 acts directly downstream of ECH1 and is also involved in the metabolism of unsaturated FAs with 4 even-numbered double bonds, showed a compromised thermoregulatory response when 5 challenged by fasting and cold exposure. Together, these studies indicate that the auxiliary 6 enzymes involved in the complete breakdown of unsaturated fatty acids are critical in the 7 adaptation to metabolic stress (e.g. fasting) by maintaining balanced FA and energy metabolism.8Our work demonstrates that ECH1 and UCP3 form a novel protein-protein interacting 9 complex that is regulated by FAs and likely important in the adaptation to metabolic stress. UCP3 10 and ECH1 directly interact at endogenous concentrations, and the presence of both proteins 11 enhances uncoupled respiration and unsaturated FA oxidation. To further characterize the 12 importance of the synergistic relationship between ECH1 and UCP3 in SKM metabolism, we 13 generated two ECH1-knockout mouse lines, and found that these mice were unable to defend their 14 core body temperature when challenged with fasting and cold-exposure, d...
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