The nucleolus stress response is coupled to an ATR-Chk1–mediated G2 arrest

Ma, Hanhui; Pederson, Thoru

doi:10.1091/mbc.e12-12-0881

Cited by 49 publications

(41 citation statements)

References 37 publications

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“…Interestingly, recent studies reported a p53-independent nucleolar stress response activated by Pol I inhibition involving the Wnttarget Peter Pan, nucleophosmin, Bax, and ATM/ATR signaling in the absence of global DNA damage. [26][27][28] Here, we demonstrate that ATM/ATR signaling contributes directly to the therapeutic efficacy of Pol I inhibition in the absence of p53.…”

Section: Discussionmentioning

confidence: 64%

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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Section: Discussionmentioning

confidence: 64%

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

Hein

Cameron

Hannan

et al. 2017

Blood

View full text Add to dashboard Cite

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“…Among the cellular pathways involved in cellular stress responses, we explored the involvement of three different kinases, that could be implicated in p53 phosphorylation, namely checkpoint kinase 1 (Chk1), checkpoint kinase 2 (Chk2) and p38 mitogen activated protein kinase (p38 MAPK). Chk1 and p38 MAPK kinases have been implicated in cellular responses to ribosomal stress thereby being good candidates for our purposes . Chk2, however, has been linked to DNA damage responses, but to our knowledge nobody has ever observed its activation in ribosomal stress so far.…”

Section: Resultsmentioning

confidence: 99%

JHDM1B expression regulates ribosome biogenesis and cancer cell growth in a p53 dependent manner

Penzo

Casoli

Pollutri

et al. 2014

Intl Journal of Cancer

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Tumors characterized by an intense ribosome biogenesis often display a more aggressive behavior. Ribosomal RNA (rRNA) synthesis is controlled at several levels, including the epigenetic regulation of the condensation of chromatin portions containing rRNA genes. JHDM1B (Jumonji C histone demethylase 1B) is a histone demethylase able to regulate the accessibility of rRNA genes. In this study, we aimed to define the contribution of JHDM1B expression to the features of breast cancer, a tumor type whose behavior is related to the rate of ribosome biogenesis. We show that, in breast cancer-derived cell lines, the increase in rRNA transcription that follows JHDM1B knock-down is mirrored by an augmented cell proliferation only in p53 compromised cells, while p53 competent cells undergo cellular senescence and death. The latter effect appears to be mediated by a p38-dependent phosphorylation of p53, inducing the expression of p15Ink4b and p21 Waf1 . In breast cancers, lower JHDM1B expression correlates with an increased size of specifically stained nucleolar organized regions, a morphological parameter directly related to the rate of ribosome biogenesis and with a poorer prognosis. In addition, in tumors lacking the controller function of p53, a lower expression of JHDM1B is associated with an increased tumor size at diagnosis. Altogether, our data indicate that epigenetic activation of rDNA genes induced by JHDM1B depletion is associated with a p53-dependent growth arrest, but may promote cancer cell growth when p53 is lacking.

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“…Importantly, the target genes are involved in both G1/S (CCNE1, CDK2, CCND1, CDK4, CDK6, and CDKN2C (p18/INK4c)) and G2/M (CDC25A, Wee1) control. It should be noted that Chek1 regulates both intra-S and G2/M checkpoints [41, 42]. Thus, it can be concluded that the majority of pa-miRNA's target genes are involved in the regulation of cell cycle checkpoints and cell cycle progression.…”

Section: Resultsmentioning

confidence: 99%

DNA damage modulates interactions between microRNAs and the 26S proteasome

et al. 2014

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26S proteasomes are known as major non-lysosomal cellular machines for coordinated and specific destruction of ubiquitinylated proteins. The proteolytic activities of proteasomes are controlled by various post-translational modifications in response to environmental cues, including DNA damage. Besides proteolysis, proteasomes also associate with RNA hydrolysis and splicing. Here, we extend the functional diversity of proteasomes by showing that they also dynamically associate with microRNAs (miRNAs) both in the nucleus and cytoplasm of cells. Moreover, DNA damage induced by an anti-cancer drug, doxorubicin, alters the repertoire of proteasome-associated miRNAs, enriching the population of miRNAs that target cell cycle checkpoint regulators and DNA repair proteins. Collectively, these data uncover yet another potential mode of action for proteasomes in the cell via their dynamic association with microRNAs.

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The nucleolus stress response is coupled to an ATR-Chk1–mediated G2 arrest

Cited by 49 publications

References 37 publications

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

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

JHDM1B expression regulates ribosome biogenesis and cancer cell growth in a p53 dependent manner

DNA damage modulates interactions between microRNAs and the 26S proteasome

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