| 1. |
- Smith, HW, et al.
(författare)
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An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2901-
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.
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| 5. |
- Liang, S, et al.
(författare)
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Polysome-profiling in small tissue samples
- 2018
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Ingår i: Nucleic acids research. - : Oxford University Press (OUP). - 1362-4962 .- 0305-1048. ; 46:1, s. e3-
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Tidskriftsartikel (refereegranskat)
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| 9. |
- Ristau, J, et al.
(författare)
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RITA requires eIF2α-dependent modulation of mRNA translation for its anti-cancer activity
- 2019
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 10:11, s. 845-
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Tidskriftsartikel (refereegranskat)abstract
- Tumor protein 53 (p53, encoded by the TP53 gene) is a key tumor suppressor regulating cell fates in response to internal and external stresses. As TP53 is mutated or silenced in a majority of tumors, reactivation of p53 by small molecules represents a promising strategy in cancer therapeutics. One such agent is RITA (reactivation of p53 and induction of tumor cell apoptosis), which restores p53 expression in cells with hyperactive HDM2 and induces apoptosis. Yet, mechanisms underlying the anticancer activity of RITA are incompletely understood. Here we show that RITA suppresses mRNA translation independently of p53 by inducing eIF2α phosphorylation. Surprisingly, reactivation of p53 following RITA treatment is critically dependent on eIF2α phosphorylation. Moreover, inhibition of eIF2α phosphorylation attenuates pro-apoptotic and anti-neoplastic effects of RITA, while inducing phosphorylation of eIF2α enhances the anticancer activity of RITA. Collectively, these findings demonstrate that the translational machinery plays a major role in determining the antineoplastic activity of RITA, and suggest that combining p53 activators and translation modulators may be beneficial.
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| 10. |
- van de Hoef, Sebastian, et al.
(författare)
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A predictive framework for dynamic heavy-duty vehicle platoon coordination
- 2019
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Ingår i: ACM Transactions on Cyber-Physical Systems. - : Association for Computing Machinery. - 2378-962X .- 2378-9638. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- This article describes a system to facilitate dynamic en route formation of heavy-duty vehicle platoons with the goal of reducing fuel consumption. Safe vehicle platooning is a maturing technology that leverages modern sensor, control, and communication technology to automatically regulate the inter-vehicle distances. Truck platooning has been shown to reduce fuel consumption through slipstreaming by up to 10% under realistic highway-driving conditions. To further benefit from this technology, a platoon coordinator is proposed, which interfaces with fleet management systems and suggests how platoons can be formed in a fuel-efficient manner over a large region. The coordinator frequently updates the plans to react to newly available information. This way, it requires a minimum of customization with respect to the logistic operations.We discuss the system architecture in detail and introduce important underlying methodological foundations. Plans are derived in computationally tractable stages optimizing fuel savings from platooning. The effectiveness of this approach is verified in a simulation study. It shows that the coordinated platooning system can improve over spontaneously occurring platooning even under the presence of disturbances. A real demonstrator has also been developed. We present data from an experiment in which three vehicles were coordinated to form a platoon on public highways under normal traffic conditions. It demonstrates the feasibility of coordinated en route platoon formation with current communication and on-board technology. Simulations and experiments support that the proposed system is technically feasible and a potential solution to the problem of using vehicle platooning in an operational context.
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