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Sökning: WFRF:(Topisirovic I)

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  • Oertlin, C, et al. (författare)
  • Generally applicable transcriptome-wide analysis of translation using anota2seq
  • 2019
  • Ingår i: Nucleic acids research. - : Oxford University Press (OUP). - 1362-4962 .- 0305-1048. ; 47:12, s. e70-
  • Tidskriftsartikel (refereegranskat)abstract
    • mRNA translation plays an evolutionarily conserved role in homeostasis and when dysregulated contributes to various disorders including metabolic and neurological diseases and cancer. Notwithstanding that optimal and universally applicable methods are critical for understanding the complex role of translational control under physiological and pathological conditions, approaches to analyze translatomes are largely underdeveloped. To address this, we developed the anota2seq algorithm which outperforms current methods for statistical identification of changes in translation. Notably, in contrast to available analytical methods, anota2seq also allows specific identification of an underappreciated mode of gene expression regulation whereby translation acts as a buffering mechanism which maintains protein levels despite fluctuations in corresponding mRNA abundance (‘translational buffering’). Thus, the universal anota2seq algorithm allows efficient and hitherto unprecedented interrogation of translatomes which is anticipated to advance knowledge regarding the role of translation in homeostasis and disease.
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  • Ristau, J, et al. (författare)
  • RITA requires eIF2α-dependent modulation of mRNA translation for its anti-cancer activity
  • 2019
  • Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 10:11, s. 845-
  • 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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