Inhibition of RNA synthesis by actinomycin D: Characteristic dose‐response of different RNA species

Perry, Robert P.; Kelley, Dawn E.

doi:10.1002/jcp.1040760202

Cited by 501 publications

(297 citation statements)

References 24 publications

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“…Actinomycin D suppresses BCL2 and MCL1 At micromolar concentrations actinomycin D is a global inhibitor of DNA-dependent transcription. 19,20 In contrast, the transcriptional response to actinomycin D in the nanomolar range in CLL cells, as used in this study, is unknown. Therefore, we treated CLL cells without del17p from four different patients with and without 20 nM actinomycin D, and after 14 h collected isolated mRNA from CD19-sorted cells, which was then used to generate cDNA.…”

Section: Identification Of P53-independent Apoptosis Inducersmentioning

confidence: 93%

“…Actinomycin D inhibits DNA-dependent RNA synthesis by binding to guanine residues, and is clinically approved for treating rare tumors such as Wilms tumor and rhabdomyosarcoma. 19,20 In CLL, it has been compared with fludarabine as a general inhibitor of RNA synthesis; however, its differential effect on individual mRNAs has not been analyzed. 21 In this study, we demonstrate that actinomycin D induced apoptosis in CLL is independent of del17p status.…”

Section: Introductionmentioning

confidence: 99%

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Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

et al. 2012

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Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in the elderly of the Western world. Although treatment options have improved over the past two decades, 10-15% of patients still have a poor prognosis and are often resistant to therapy. Aberrations in the p53 pathway, such as a deleted (del17p13) or mutated p53 gene, are highly enriched in this class of patients. In an extensive screen for p53-independent apoptosis inducers, actinomycin D was identified from 1496 substances and shown to induce apoptosis in primary CLL cells derived from high-risk patients including those with aberrant p53, revealing a novel p53-independent mechanism of action. Both pro-survival genes BCL2 and MCL1 are targeted by actinomycin D, in contrast to fludarabine the backbone of current treatment schedules. In the well-established TCL1 transgenic mouse model for high-risk CLL, actinomycin D treatment was more effective in reducing tumor load than fludarabine, with no evidence of resistance after three treatment cycles and an overall survival increase of over 300%. Tumor load reduction was coupled to BCL2 downregulation. Our results identify the clinically approved compound actinomycin D as a potentially valuable treatment option for CLL high-risk patients.

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Section: Identification Of P53-independent Apoptosis Inducersmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

et al. 2012

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“…5E) 25,47 . However, application of MLN4924 did not cause any detectable changes in rRNA production (Fig.…”

Section: Mln4924 Alters the Composition Of The Nucleolar Proteome Butmentioning

confidence: 99%

“…For example, the p53 tumour suppressor responds to the majority of known nucleolar stressors, with the best characterized being the inhibition of RNA Pol I transcription 24 . Low doses of ActD specifically inhibit RNA Pol I and thus the production of rRNA in the nucleolus 25 . Under these conditions, several RPs have been reported to block Mdm2 E3-ligase activity towards p53 through direct binding to Mdm2.…”

Section: Introductionmentioning

confidence: 99%

The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway

et al. 2015

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The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway Bailly, A.; Perrin, A.; Bou Malhab, L. J.; Pion, E.; Larance, M.; Nagala, M.; Smith, P.; O'Donohue, M.-F.; Gleizes, P.-E.; Zomerdijk, Josephus; Lamond, Angus; Xirodimas, D. P. Published in: Oncogene DOI:10.1038/onc.2015.104 Publication date: 2016 Document VersionPeer reviewed version Link to publication in Discovery Research Portal Citation for published version (APA):Bailly, A., Perrin, A., Bou Malhab, L. J., Pion, E., Larance, M., Nagala, M., ... Xirodimas, D. P. (2016). The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway. Oncogene, 35(4), 415-426. DOI: 10.1038415-426. DOI: 10. /onc.2015 General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain.• You may freely distribute the URL identifying the publication in the public portal. Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

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“…B23-hnRNPU interaction was induced by inhibition of RNA Pol I transcription ActD is a chemical agent, which inhibits activities of RNA Polymerase I and II and induces DNA damage (Perry and Kelley, 1970). To define whether B23-hnRNPU interaction was induced by ActD-caused transcription inhibition or by translational inhibition, both ActD and CHX (cycloheximide, a eukaryotic translational inhibitor) were used.…”

Section: B23 Binds To Hnrnpu and Hnrnpa1 In The Cytosol In Response Tmentioning

confidence: 99%

B23 acts as a nucleolar stress sensor and promotes cell survival through its dynamic interaction with hnRNPU and hnRNPA1

et al. 2010

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Inhibition of RNA synthesis by actinomycin D: Characteristic dose‐response of different RNA species

Abstract: A quantitative dose-response study was made of the inhibition by actinomycin D of the synthesis of various RNA species in cultured L cells. After a suitable

Cited by 501 publications

References 24 publications

Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway

B23 acts as a nucleolar stress sensor and promotes cell survival through its dynamic interaction with hnRNPU and hnRNPA1

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