S6 Kinase is essential for MYC-dependent rDNA transcription in Drosophila

Mitchell, Naomi C; Tchoubrieva, Elissaveta B; Chahal, Arjun; Woods, Simone; Lee, Amanda; Lin, Jane I.; Parsons, Linda M.; Jastrzebski, Katarzyna; Poortinga, Gretchen; Hannan, Katherine M.; Pearson, Richard B.; Hannan, Ross D.; Quinn, Leonie M.

doi:10.1016/j.cellsig.2015.07.018

Cited by 16 publications

(11 citation statements)

References 78 publications

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“…Of note, d-S6K phosphorylation may amplify the effects of d-myc over-expression [63]. The ratio between phosphorylated and un-phosphorylated d-S6K of BicC tubules was found to be twice as high as the wild-type, but rapamycin treatment restored wild-type levels.…”

Section: Discussionmentioning

confidence: 99%

Bicaudal C mutation causes myc and TOR pathway up-regulation and polycystic kidney disease-like phenotypes in Drosophila

et al. 2017

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Progressive cystic kidney degeneration underlies diverse renal diseases, including the most common cause of kidney failure, autosomal dominant Polycystic Kidney Disease (PKD). Genetic analyses of patients and animal models have identified several key drivers of this disease. The precise molecular and cellular changes underlying cystogenesis remain, however, elusive. Drosophila mutants lacking the translational regulator Bicaudal C (BicC, the fly ortholog of vertebrate BICC1 implicated in renal cystogenesis) exhibited progressive cystic degeneration of the renal tubules (so called “Malpighian” tubules) and reduced renal function. The BicC protein was shown to bind to Drosophila (d-) myc mRNA in tubules. Elevation of d-Myc protein levels was a cause of tubular degeneration in BicC mutants. Activation of the Target of Rapamycin (TOR) kinase pathway, another common feature of PKD, was found in BicC mutant flies. Rapamycin administration substantially reduced the cystic phenotype in flies. We present new mechanistic insight on BicC function and propose that Drosophila may serve as a genetically tractable model for dissecting the evolutionarily-conserved molecular mechanisms of renal cystogenesis.

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Section: Discussionmentioning

confidence: 99%

Bicaudal C mutation causes myc and TOR pathway up-regulation and polycystic kidney disease-like phenotypes in Drosophila

et al. 2017

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“…As a key downstream effector of mTORC1, S6K1 has been reported to cooperate with MYC to modulate rDNA transcription through RRN3 in Drosophila [63] and regulate the ribosome biogenesis transcriptional program, specifically by altering the transcription of nucleolar factors required for rRNA synthesis, cleavage, post-transcriptional modifications, ribosome assembly and transport [64]. Recently two groups independently demonstrated that mTORC1-S6K1 signaling promoted de novo -synthesis of pyrimidines and their incorporation into RNA and DNA, which is required for ribosome biogenesis and cell growth, in response to growth factors and nutrients [65, 66].…”

Section: Discussionmentioning

confidence: 99%

Amino acid-dependent signaling via S6K1 and MYC is essential for regulation of rDNA transcription

et al. 2016

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Dysregulation of RNA polymerase I (Pol I)-dependent ribosomal DNA (rDNA) transcription is a consistent feature of malignant transformation that can be targeted to treat cancer. Understanding how rDNA transcription is coupled to the availability of growth factors and nutrients will provide insight into how ribosome biogenesis is maintained in a tumour environment characterised by limiting nutrients. We demonstrate that modulation of rDNA transcription initiation, elongation and rRNA processing is an immediate, co-regulated response to altered amino acid abundance, dependent on both mTORC1 activation of S6K1 and MYC activity. Growth factors regulate rDNA transcription initiation while amino acids modulate growth factor-dependent rDNA transcription by primarily regulating S6K1-dependent rDNA transcription elongation and processing. Thus, we show for the first time amino acids regulate rRNA synthesis by a distinct, post-initiation mechanism, providing a novel model for integrated control of ribosome biogenesis that has implications for understanding how this process is dysregulated in cancer.

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“…The Yki human orthologue YAP is indeed found overexpressed in a number of human cancers [ 104 ], including GBM [ 105 ]. Moreover, it is known that aPKC activation increases MYC levels through deregulation of the Hippo pathway both in Drosophila [ 77 ] and in mammals [ 106 ], while PI3K activation is known to regulate MYC stability and MYC-dependent transcription in Drosophila [ 107 , 108 ], as it happens in mammals [ 109 ]. Finally, c-MYC is known to inhibit PTEN by upregulating miR-26A in GBM [ 110 ], thus creating a vicious circle.…”

Section: Resultsmentioning

confidence: 99%

Failure of the PTEN/aPKC/Lgl Axis Primes Formation of Adult Brain Tumours inDrosophila

Paglia

Sollazzo

Giacomo

et al. 2017

BioMed Research International

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Different regions in the mammalian adult brain contain immature precursors, reinforcing the concept that brain cancers, such as glioblastoma multiforme (GBM), may originate from cells endowed with stem-like properties. Alterations of the tumour suppressor gene PTEN are very common in primary GBMs. Very recently, PTEN loss was shown to undermine a specific molecular axis, whose failure is associated with the maintenance of the GBM stem cells in mammals. This axis is composed of PTEN, aPKC, and the polarity determinant Lethal giant larvae (Lgl): PTEN loss promotes aPKC activation through the PI3K pathway, which in turn leads to Lgl inhibition, ultimately preventing stem cell differentiation. To find the neural precursors responding to perturbations of this molecular axis, we targeted different neurogenic regions of the Drosophila brain. Here we show that PTEN mutation impacts aPKC and Lgl protein levels also in Drosophila. Moreover, we demonstrate that PI3K activation is not sufficient to trigger tumourigenesis, while aPKC promotes hyperplastic growth of the neuroepithelium and a noticeable expansion of the type II neuroblasts. Finally, we show that these neuroblasts form invasive tumours that persist and keep growing in the adult, leading the affected animals to untimely death, thus displaying frankly malignant behaviours.

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S6 Kinase is essential for MYC-dependent rDNA transcription in Drosophila

Cited by 16 publications

References 78 publications

Bicaudal C mutation causes myc and TOR pathway up-regulation and polycystic kidney disease-like phenotypes in Drosophila

Bicaudal C mutation causes myc and TOR pathway up-regulation and polycystic kidney disease-like phenotypes in Drosophila

Amino acid-dependent signaling via S6K1 and MYC is essential for regulation of rDNA transcription

Failure of the PTEN/aPKC/Lgl Axis Primes Formation of Adult Brain Tumours inDrosophila

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