Inhibition of nucleoplasmic transcription and the translation of rapidly labeled nuclear proteins by low concentrations of actinomycin D in vivo. Proposed role of messenger RNA in ribosomal RNA transcription

Lindell, Thomas J.; O'Malley, Anthony F.; Puglisi, Brian

doi:10.1021/bi00600a003

Cited by 33 publications

(3 citation statements)

References 57 publications

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“…The inhibition of pre-rRNA synthesis in mammalian cells by cycloheximide or other antibiotics was previously reported by several investigators, leading to the hypothesis that the normal rate of transcription of the rRNA genes is supported by continuous synthesis of some protein(s) with a rapid turnover (Tsukada & Lieberman, 1965;Muramatsu et al, 1970;Gross & Pogo, 1974;Franze-Fernandez & Fontanive-Sengiiesa, 1973;Lampert & Feigelson, 1974;Gross & Pogo, 1974;Lindell et al, 1978). Although some workers questioned the idea (Farber & Farmer, 1973;Grummt & Grummt, 1976;Stoyanova & Dabeva, 1980), Mishima et al (1979 and Haim et al (1983), using cycloheximide and pactamycin respectively, presented data supporting the participation of short-lived protein(s) in pre-rRNA synthesis.…”

Section: Discussionmentioning

confidence: 88%

Effects of glucocorticoid and cycloheximide on the activity and amount of RNA polymerase I in nuclei of rat liver

Matsui¹,

Yazawa²,

Suzuki³

et al. 1986

Biochemical Journal

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The activity of the template-engaged form of RNA polymerase I from livers of adrenalectomized rats was about 50-60% of that of normal control rats, and increased about 2-fold at 6 h after the administration of dexamethasone. However, no change was found in the activity of the 'free' form of RNA polymerase I or the template-engaged form of RNA polymerase II. Immunochemical studies using guinea-pig anti-(RNA polymerase I) serum disclosed that the total number of RNA polymerase I molecules did not vary during the treatment with dexamethasone. Cycloheximide caused a rapid decrease in the template-engaged form of RNA polymerase I activity in normal rats and in dexamethasone-treated (6 h) adrenalectomized rats, to the value in adrenalectomized rats, but affected it only slightly in adrenalectomized rats. The elongation rate of rRNA-precursor synthesis in liver nuclei was not affected by a change in the concentration of circulating dexamethasone. From these results, it is concluded that about half the rRNA-precursor synthesis in rat liver is regulated by glucocorticoids, probably through the synthesis of short-lived protein(s) which may play a role in conversion of the 'dormant' form of RNA polymerase I into the 'engaged' form.

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Section: Discussionmentioning

confidence: 88%

Effects of glucocorticoid and cycloheximide on the activity and amount of RNA polymerase I in nuclei of rat liver

Matsui¹,

Yazawa²,

Suzuki³

et al. 1986

Biochemical Journal

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“…Moreover, the sensitivity was not restricted to MLL-driven AML. To support our findings that the antileukemic effect of CX-5461 is due to on-target inhibition of Pol I transcription, 7 AML cell lines were tested for their sensitivity to 2 additional Pol I inhibitors, BMH-21 14 and low-dose ActD, 15 and an inactive compound (CX-5447), which is structurally similar to CX-5461. 7,16 Both BMH-21 and ActD decreased cell viability after 48 hours in 7 AML cell lines with the level of sensitivity broadly correlating with that of CX-5461 ( Figure 3F).…”

Section: Aml Cells Are Highly Sensitive To Inhibition Of Pol I Transcmentioning

confidence: 99%

Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population

Hein

Cameron

Hannan

et al. 2017

Blood

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Key Points• Inhibition of RNA Pol I by CX-5461 treats aggressive AML and outperforms standard chemotherapy regimens.• CX-5461 induces p53-dependent apoptosis, p53-independent cell-cycle defects and differentiation, and reduces LICs.Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of this new class of inhibitors to treat highly aggressive AML by targeting LICs. (Blood. 2017;129(21):2882-2895

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“…9). Because the synthesis of ribosomes depends of specific mRNA molecules blocked by A-D, the incorporation of uridine in rRNA was measured as a reliable index of the total mRNA inhibition (Lindell et al, 1978).…”

Section: Uptake Of Labelled Uridine Into Rnamentioning

confidence: 99%

Requirement of RNA synthesis for pathfinding by growing axons

Bernhardi¹,

Bastiani²

1995

J of Comparative Neurology

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The effects of actinomycin D were studied in cultured grasshopper embryos at different stages of development by following the outgrowth patterns of identified neurones known as aCC, pCC, and Q1. When administered at stages occurring before 31% of embryonic development, actinomycin D (0.05-0.10 microM for 24-48 hours) prevented axon extension, whereas it did not affect the development of the nervous system in embryos older than 34% of development. At 31-34% of development, actinomycin D perturbed pathfinding of aCC without blocking axon extension. Thus, only 22% of the aCCs (n = 271) in embryos treated with actinomycin D extended an axon along the intersegmental nerve as in control embryos. In the remaining embryos, aCC failed to turn into the intersegmental nerve root; its growth cone remained in the longitudinal connective, above or below the turning point. Neurones of the group caudal to the intersegmental nerve root could extend along either the anterior or posterior commissure of the next posterior segment. In contrast to the observations made with aCC, only 1.2% of pCC (n = 166) and 0.0% of Q1 (n = 45) in embryos treated with actinomycin D showed axon growth along aberrant pathways. The position of the growth cones of most pCCs and all Q1s observed were in various points along their normal pathway. Both pCC and Q1, as a population, showed an extension rate significantly lower than that of their control counterparts. The effect of actinomycin D on aCC pathway choice was probably mediated by inhibition of RNA synthesis, because incorporation of uridine into RNA was reduced by 40%. The labelling of several monoclonal antibodies (1C10, 3B11, 7F7) that recognise surface glycoproteins (lachesin, fasciclin I, and REGA-1) involved in nervous system development of grasshopper embryos was suppressed. Our results suggest that the navigation of some axons along different pathways requires the synthesis of new mRNA.

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Inhibition of nucleoplasmic transcription and the translation of rapidly labeled nuclear proteins by low concentrations of actinomycin D in vivo. Proposed role of messenger RNA in ribosomal RNA transcription

Cited by 33 publications

References 57 publications

Effects of glucocorticoid and cycloheximide on the activity and amount of RNA polymerase I in nuclei of rat liver

Effects of glucocorticoid and cycloheximide on the activity and amount of RNA polymerase I in nuclei of rat liver

Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population

Requirement of RNA synthesis for pathfinding by growing axons

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