Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development

Grewal, Savraj; Li, Ling; Orian, Amir; Eisenman, Robert N.; Edgar, Bruce A.

doi:10.1038/ncb1223

Cited by 363 publications

(401 citation statements)

References 35 publications

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“…Insulin and IGF-1 stimulate the activity of polymerase I transcription by elevating both UBF protein level and phosphorylation (Hannan et al, 1998;Wu et al, 2005). Partial hepatectomy induces a progressive increase in rRNA synthesis (up to 24 h after operation) in regenerating rat hepatocytes (Sirri et al, 1995) very likely due to the induction of c-myc (Thompson et al, 1986), which controls the RNA polymerase I activity (Arabi et al, 2005;Grandori et al, 2005;Grewal et al, 2005). Cortisol at the dose used in the present experiments stimulated rRNA transcription in rat hepatocytes (Sirri et al, 1995) by activating the glycocorticoid receptor signalling (Glibetic et al, 1993), while inhibiting their proliferation (Nadal, 1995).…”

Section: Polr1a Silencing Stabilises P53 Without Disrupting the Nuclementioning

confidence: 99%

The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells

et al. 2011

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Data on the relationship between ribosome biogenesis and p53 function indicate that the tumour suppressor can be activated by either nucleolar disruption or ribosomal protein defects. However, there is increasing evidence that the induction of p53 does not always require these severe cellular changes, and data are still lacking on a possible role of ribosome biogenesis in the downregulation of p53. Here, we studied the effect of the up-and downregulation of the rRNA transcription rate on p53 induction in mammalian cells. We found that a downregulation of rRNA synthesis, induced by silencing the POLR1A gene coding for the RNA polymerase I catalytic subunit, stabilised p53 without altering the nucleolar integrity in human cancer cells. p53 stabilisation was due to the inactivation of the MDM2-mediated p53 degradation by the binding of ribosomal proteins no longer used for ribosome building. p53 stabilisation did not occur when rRNA synthesis downregulation was associated with a contemporary reduction of protein synthesis. Furthermore, we demonstrated that in three different experimental models characterised by an upregulation of rRNA synthesis, cancer cells treated with insulin or exposed to the insulin-like growth factor 1, rat liver stimulated by cortisol and regenerating rat liver after partial hepatectomy, the p53 protein level was reduced due to a lowered ribosomal protein availability for MDM2 binding. It is worth noting that the upregulation of rRNA synthesis was responsible for a decreased p53-mediated response to cytotoxic stresses. These findings demonstrated that the balance between rRNA and ribosomal protein synthesis controls the function of p53 in mammalian cells, that p53 can be induced without the occurrence of severe changes of the cellular components controlling ribosome biogenesis, and that conditions characterised by an upregulated rRNA synthesis are associated with a reduced p53 response.

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Section: Polr1a Silencing Stabilises P53 Without Disrupting the Nuclementioning

confidence: 99%

The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells

et al. 2011

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“…The increase in expression of pre-rRNA by dMyc overexpression is accompanied by a dramatic increase in nucleolar size, a good indicator of increased ribosome activity [34]. This effect is not observed when other growth regulating factors, such as the PI3K, Dp110, or Cyclin D/Cdk4 are overexpressed (de la Cova & Johnston, unpublished data) [34].…”

Section: Dmyc Activity Makes More Ribosomesmentioning

confidence: 99%

“…For example, RpI135 mRNA, encoding a Pol I subunit, is rapidly increased within 4 h of dMyc expression, as is dTIF-IA, a growth-regulated Pol I-associated factor. This rapid response occurs even before an increase in the synthesis of pre-processed rRNA is detected [34].…”

Section: Identifying Dmyc Target Genesmentioning

confidence: 99%

“…Most of these dMyc-dependent targets encode factors involved in RNA binding, rRNA processing, nucleolar function, and ribosome biogenesis, and include, for example, the nucleolar proteins Fibrillarin and CG1542, which are involved in processing of the 35S primary transcript and of 27S pre-rRNA, respectively [33]. A majority of the targets that are down-regulated by dmyc RNAi are induced by overexpression of dMyc in S2 cells, or in experiments using RNA from whole larvae in which dMyc is overexpressed [17,34]. Again, genes involved in ribosome biogenesis dominate the targets increased by dMyc: one-fifth of transcripts up-regulated by dMyc expression encode factors used in ribosome biogenesis [17,33,34].…”

Section: Identifying Dmyc Target Genesmentioning

confidence: 99%

“…A majority of the targets that are down-regulated by dmyc RNAi are induced by overexpression of dMyc in S2 cells, or in experiments using RNA from whole larvae in which dMyc is overexpressed [17,34]. Again, genes involved in ribosome biogenesis dominate the targets increased by dMyc: one-fifth of transcripts up-regulated by dMyc expression encode factors used in ribosome biogenesis [17,33,34]. These targets include RNA Polymerase I-and IItranscribed genes, and many appear to be directly responsive to dMyc activity.…”

Section: Identifying Dmyc Target Genesmentioning

confidence: 99%

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Myc in model organisms: A view from the flyroom

Cova

Johnston

2006

Seminars in Cancer Biology

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The Myc transcription factor regulates fundamental processes in a cell's life: its growth, division, and survival. Myc is conserved throughout metazoan phyla, and its identification in the fruit fly, Drosophila melanogaster has led to new insights in Myc's physiological roles. In this review, we describe recent research on the biology of Myc and its family members in Drosophila, paying particular attention to its role in the control of growth during development.

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EBP2, a novel NPM‐ALK‐interacting protein in the nucleolus, contributes to the proliferation of ALCL cells by regulating tumor suppressor p53

et al. 2020

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The oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), found in anaplastic large cell lymphoma (ALCL), localizes to the cytosol, nucleoplasm, and nucleolus. However, the relationship between its localization and transforming activity remain unclear. We herein demonstrated that NPM-ALK localized to the nucleolus by binding to nucleophosmin 1 (NPM1), a nucleolar protein that exhibits shuttling activity between the nucleolus and cytoplasm, in a manner that was dependent on its kinase activity. In the nucleolus, NPM-ALK interacted with EBNA1-binding protein 2 (EBP2), which is involved in rRNA biosynthesis. Moreover, enforced expression of NPM-ALK induced tyrosine phosphorylation of EBP2. Knockdown of EBP2 promoted the activation of the tumor suppressor p53, leading to G 0 /G 1-phase cell cycle arrest in Ba/F3 cells transformed by NPM-ALK and ALCL patient-derived Ki-JK cells, but not ALCL patient-derived SUDH-L1 cells harboring p53 gene mutation. In Ba/F3 cells transformed by NPM-ALK and Ki-JK cells, p53 activation induced by knockdown of EBP2 was significantly inhibited by Akt inhibitor GDC-0068, mTORC1 inhibitor rapamycin, and knockdown of Raptor, 2.3. Cell culture, retrovirus infection and transfection The IL-3-dependent hematopoietic cell line Ba/F3 cells were cultured in RPMI-1640 medium (Nacalai Tesque) containing 10% heat-inactivated fetal bovine serum (FBS) (BioWest, Nuaille, France), 100 units/ml penicillin (Nacalai Tesque), 100 g/ml streptomycin (Nacalai Tesque), 2 ng/mL IL-3 (PEPROTECH), and 5 g/mL puromycin (InVivoGen). Ki-JK cells and SUDH-L1 cells, derived from NPM-ALK-positive ALCL patients, were cultured in RPMI-1640 medium supplemented with 10% FBS, 100 units/ml penicillin, and 100 g/ml streptomycin. HEK293T cells were cultured in Dulbecco's Modified Eagle Medium (DMEM)-High Glucose supplemented with 10% FBS, 100 units/ml penicillin, and 100 g/ml streptomycin. NPM1 −/− /p53 −/− MEF and p53 −/− MEF were kindly gifted from Dr. Pandolfi (Harvard University) and cultured in DMEM-High Glucose (Nacalai Tesque) supplemented with 10% FBS, 100 units/ml penicillin, 100 g/ml streptomycin, and 55 M 2-mercaptoethanol (Nacalai Tesque). Ba/F3 cells were infected using RetroNectin (Takara Bio Inc., Shiga, Japan) and MEFs were infected using 10 g/ml polybrene as reported previously [16]. HEK293T cells were transfected with plasmids using polyethylenimine (PEI) Max (Polyscience inc. Warrington, PA, USA). 2.4. Fractionation of cells into cytosolic, nucleoplasmic, and nucleolar fractions We conducted fractionation as described previously [22]. Briefly, cells were suspended in mild detergent buffer (20 mM Tris pH7.4, 10 mM KCl, 3 mM MgCl 2 , 0.1% NP-40, and 10% glycerol) and centrifuged at 1,400×g at 4°C for 10 min, and the resulting supernatant was prepared as the cytosolic fraction. Nuclear pellets were then resuspended in 0.25 M sucrose/10 mM MgCl 2 , layered over a cushion of 0.35 M sucrose/0.5 mM MgCl 2 , and centrifuged at 1,400×g at 4°C for 5 min. The resulting nuclear pellet was re...

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Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development

Cited by 363 publications

References 35 publications

The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells

The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells

Myc in model organisms: A view from the flyroom

EBP2, a novel NPM‐ALK‐interacting protein in the nucleolus, contributes to the proliferation of ALCL cells by regulating tumor suppressor p53

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