التفاصيل البيبلوغرافية
| العنوان: |
Transcriptional-translational conflict is a barrier to cellular transformation and cancer progression. |
| المؤلفون: |
Jana, Sujata1 (AUTHOR), Brahma, Sandipan2 (AUTHOR), Arora, Sonali1 (AUTHOR), Wladyka, Cynthia L.1 (AUTHOR), Hoang, Patrick1 (AUTHOR), Blinka, Steven1,3 (AUTHOR), Hough, Rowan1 (AUTHOR), Horn, Jessie L.1 (AUTHOR), Liu, Yuzhen1 (AUTHOR), Wang, Li-Jie1 (AUTHOR), Depeille, Philippe4 (AUTHOR), Smith, Eric4 (AUTHOR), Montgomery, Robert B.3 (AUTHOR), Lee, John K.1,3,5 (AUTHOR), Haffner, Michael C.1,5 (AUTHOR), Vakar-Lopez, Funda5 (AUTHOR), Grivas, Petros3 (AUTHOR), Wright, Jonathan L.6 (AUTHOR), Lam, Hung-Ming6 (AUTHOR), Black, Peter C.7 (AUTHOR) |
| المصدر: |
Cancer Cell. May2023, Vol. 41 Issue 5, p853-853. 1p. |
| مصطلحات موضوعية: |
*DNA repair, *CANCER invasiveness, *GENETIC translation, *UROTHELIUM, *CELL transformation, *PROTEIN synthesis |
| مستخلص: |
We uncover a tumor-suppressive process in urothelium called transcriptional-translational conflict caused by deregulation of the central chromatin remodeling component ARID1A. Loss of Arid1a triggers an increase in a nexus of pro-proliferation transcripts, but a simultaneous inhibition of the eukaryotic elongation factor 2 (eEF2), which results in tumor suppression. Resolution of this conflict through enhancing translation elongation speed enables the efficient and precise synthesis of a network of poised mRNAs resulting in uncontrolled proliferation, clonogenic growth, and bladder cancer progression. We observe a similar phenomenon in patients with ARID1A-low tumors, which also exhibit increased translation elongation activity through eEF2. These findings have important clinical implications because ARID1A-deficient, but not ARID1A-proficient, tumors are sensitive to pharmacologic inhibition of protein synthesis. These discoveries reveal an oncogenic stress created by transcriptional-translational conflict and provide a unified gene expression model that unveils the importance of the crosstalk between transcription and translation in promoting cancer. [Display omitted] • Transcriptional-translational conflict is tumor suppressive in bladder epithelium • De-repression of translation elongation enables oncogenic phenotypes • ARID1A-low tumors are sensitive to drug-induced transcriptional-translational conflict • Impaired DNA damage response is a collateral effect of gene expression conflict Jana et al. reveal that ARID1A orchestrates a molecular conflict between gene-specific DNA transcription and mRNA translation in the bladder epithelium that is tumor suppressive. Transcriptional-translational conflict represents a new molecular stress that protects cells from transformation and must be overcome to enable cancer phenotypes. [ABSTRACT FROM AUTHOR] |
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