Journal
CELL
Volume 175, Issue 3, Pages 766-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.09.027
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Funding
- NCI NIH HHS [P30 CA060553, R01 CA214035, T32 CA070085, R50 CA211428] Funding Source: Medline
- NINDS NIH HHS [R01 NS093079] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [P30CA060553, T32CA070085, R50CA211428, R01CA214035] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS093079] Funding Source: NIH RePORTER
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The super elongation complex (SEC) is required for robust and productive transcription through release of RNA polymerase II (Pol II) with its P-TEFb module and promoting transcriptional processivity with its ELL2 subunit. Malfunction of SEC contributes to multiple human diseases including cancer. Here, we identify peptidomimetic lead compounds, KL-1 and its structural homolog KL-2, which disrupt the interaction between the SEC scaffolding protein AFF4 and P-TEFb, resulting in impaired release of Pol II from promoter-proximal pause sites and a reduced average rate of processive transcription elongation. SEC is required for induction of heat-shock genes and treating cells with KL-1 and KL-2 attenuates the heat-shock response from Drosophila to human. SEC inhibition downregulates MYC and MYC-dependent transcriptional programs in mammalian cells and delays tumor progression in a mouse xenograft model of MYC-driven cancer, indicating that small-molecule disruptors of SEC could be used for targeted therapy of MYC-induced cancer.
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