Functional ribosome biogenesis is a prerequisite for p53 destabilization: impact of chemotherapy on nucleolar functions and RNA metabolism

Burger, Kaspar; Eick, Dirk

doi:10.1515/hsz-2013-0153

Cited by 29 publications

(27 citation statements)

References 107 publications

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“…It is well established that inhibition of rRNA maturation leads to impaired ribosome biogenesis and induction of nucleolar stress32, which may be evidenced by small nucleoli, nucleolar disorganization33 and p53 stabilization3234. Indeed, immunofluorescent stainings of PES1 (Fig.…”

Section: Resultsmentioning

confidence: 96%

Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans

et al. 2016

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Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease.

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Section: Resultsmentioning

confidence: 96%

Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans

et al. 2016

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“…Burger et al . observed that inhibition of ribosome biogenesis, including rRNA metabolic processes, by the chemotherapeutic drugs flavopiridol and 5-fluorouracil could potentially increase the efficacy of therapeutic treatment in human fibrosarcoma23. In addition, chemotherapeutic drugs induce DNA damage, which is a mechanism that allows cells to repair damage and confer resistance to anticancer drugs24.…”

Section: Resultsmentioning

confidence: 99%

Phosphoproteomics Reveals HMGA1, a CK2 Substrate, as a Drug-Resistant Target in Non-Small Cell Lung Cancer

Wang

Pan

Tsai

et al. 2017

Sci Rep

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Although EGFR tyrosine kinase inhibitors (TKIs) have demonstrated good efficacy in non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations, most patients develop intrinsic and acquired resistance. We quantitatively profiled the phosphoproteome and proteome of drug-sensitive and drug-resistant NSCLC cells under gefitinib treatment. The construction of a dose-dependent responsive kinase-substrate network of 1548 phosphoproteins and 3834 proteins revealed CK2-centric modules as the dominant core network for the potential gefitinib resistance-associated proteins. CK2 knockdown decreased cell survival in gefitinib-resistant NSCLCs. Using motif analysis to identify the CK2 core sub-network, we verified that elevated phosphorylation level of a CK2 substrate, HMGA1 was a critical node contributing to EGFR-TKI resistance in NSCLC cell. Both HMGA1 knockdown or mutation of the CK2 phosphorylation site, S102, of HMGA1 reinforced the efficacy of gefitinib in resistant NSCLC cells through reactivation of the downstream signaling of EGFR. Our results delineate the TKI resistance-associated kinase-substrate network, suggesting a potential therapeutic strategy for overcoming TKI-induced resistance in NSCLC.

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“…The nucleolus forms during G 1 phase around rDNA clusters termed nucleolar organizing regions (1). The rRNA precursors are transcribed by RNA polymerase I, assembled, and processed by the ribosome biogenesis machinery in a tightly regulated mechanism (2,3).…”

mentioning

confidence: 99%

The Wnt Target Protein Peter Pan Defines a Novel p53-independent Nucleolar Stress-Response Pathway

Pfister

Keil

Kühl

2015

Journal of Biological Chemistry

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Background: Peter Pan (PPAN) localizes to nucleoli and functions in ribosome biogenesis. Results: PPAN localizes also to mitochondria, and PPAN knockdown triggers p53-independent mitochondrial apoptosis and nucleolar stress as observed by de-stabilization of nucleophosmin. Conclusion: PPAN orchestrates a p53-independent stress-response pathway by coupling nucleolar stress induction to the mitochondrial apoptosis. Significance: Novel insight into the anti-apoptotic role of the ribosome processing factor PPAN is provided.

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Functional ribosome biogenesis is a prerequisite for p53 destabilization: impact of chemotherapy on nucleolar functions and RNA metabolism

Cited by 29 publications

References 107 publications

Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans

Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans

Phosphoproteomics Reveals HMGA1, a CK2 Substrate, as a Drug-Resistant Target in Non-Small Cell Lung Cancer

The Wnt Target Protein Peter Pan Defines a Novel p53-independent Nucleolar Stress-Response Pathway

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