TIF-IA: An oncogenic target of pre-ribosomal RNA synthesis

Jin, Rui; Zhou, Wei

doi:10.1016/j.bbcan.2016.09.003

Cited by 19 publications

(28 citation statements)

References 91 publications

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“…It is well documented that the phosphorylation status of TIF-IA is modulated in response to environmental and cytotoxic stress so that rates of rRNA transcription can be adjusted accordingly (37). Here we identify an alternative mechanism by which stress can act on the PolI complex involving degradation of TIF-IA.…”

Section: Identification Of a Novel Pathway To Tif-ia Inactivationmentioning

confidence: 86%

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Identification of a novel, NF-κB nucleolar stress response pathway

Chen

Lobb

Morin

et al. 2017

Preprint

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Abstractp53 as an effector of nucleolar stress is well defined, but p53 independent mechanisms are largely unknown. Like p53, the NF-κB transcription factor plays a critical role in maintaining cellular homeostasis under stress. Many stresses that stimulate NF-κB also disrupt nucleoli. However, the link between nucleolar function and activation of the NF-κB pathway is as yet unknown. Here we demonstrate that siRNA silencing of PolI complex components stimulates NF-κB signalling. Unlike p53 nucleolar stress response, this effect does not appear to be linked to inhibition of rDNA transcription. We show that specific stress stimuli of NF-κB induce degradation of a critical component of the PolI complex, TIF-IA. This degradation precedes activation of the NF-κB pathway and is associated with an atypical nucleolar architecture. It is mimicked by CDK4 inhibition and is dependent upon upstream binding factor (UBF) and p14ARF. We show that blocking stress effects on TIF-IA blocks their ability to activate the NF-κB pathway. Finally, using ex vivo culture, we show a strong correlation between degradation of TIF-IA and activation of NF-κB in freshly resected, human colorectal tumours exposed to the chemopreventative agent, aspirin. Together, our study provides compelling evidence for a new, NF-κB nucleolar stress response pathway that has in vivo relevance and therapeutic implications.not peer-reviewed)

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Section: Identification Of a Novel Pathway To Tif-ia Inactivationmentioning

confidence: 86%

“…TIF-IA is essential for rDNA transcription as it tethers Pol I to the rDNA promoter (37,38). It is also the component of the pre-initiation complex that is targeted by stress/environmental signals to alter PolI activity (39,40).…”

Section: Degradation Of Tif-ia Precedes Nf-κb Pathway Activationmentioning

confidence: 99%

Identification of a novel, NF-κB nucleolar stress response pathway

Chen

Lobb

Morin

et al. 2017

Preprint

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“…TIF-IA is the master regulator of PolI-driven transcription [35,51]. Not only is it essential for anchoring PolI to the rDNA promotor, it is also the component of the PIC that transduces environmental signals to the PolI transcriptional machinery.…”

Section: Tif-ia-nf-κb Nucleolar Stress Responsementioning

confidence: 99%

“…Not only is it essential for anchoring PolI to the rDNA promotor, it is also the component of the PIC that transduces environmental signals to the PolI transcriptional machinery. Upon exposure of cells to exogenous stresses, TIF-IA is targeted by a complex network of kinases and phosphatases including mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), extracellular signal-regulated kinase (ERK), and protein phosphatase 2A (PP2A), which activate or inactivate the protein to fine-tune the transcriptional output [51][52][53][54]. The consequences of TIF-IA inactivation are context dependent but in general, its loss leads to cell cycle arrest and apoptosis, confirming the importance of this protein as a critical regulator of cellular homeostasis [55][56][57].…”

Section: Tif-ia-nf-κb Nucleolar Stress Responsementioning

confidence: 99%

“…In general, nucleolar segregation is associated with a reduction in nucleolar size and phosphorylation-mediated inactivation of TIF-IA has been implicated in this effect [51,54,56]. However, in contrast to phosphorylation-mediated inactivation, degradation of TIF-IA causes a striking increase in nucleolar size, alongside inhibition of rDNA transcription and segregation of nucleolar components (Figure 3) [1].…”

Section: Tif-ia Nucleolar Enlargement and Activation Of The Nf-κb Pmentioning

confidence: 99%

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Insights into the Relationship between Nucleolar Stress and the NF-κB Pathway

Chen

Stark

2019

Trends in Genetics

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The nuclear organelle the nucleolus and the transcription factor nuclear factor of κ-light-chain-enhancer of activated B cells (NF-κB) are both central to the control of cellular homeostasis, dysregulated in common diseases and implicated in the ageing process. Until recently, it was believed that they acted independently to regulate homeostasis in health and disease. However, there is an emerging body of evidence suggesting that nucleoli and NF-κB signalling converge at multiple levels. Here we will review current understanding of this crosstalk. We will discuss activation of the NF-κB pathway by nucleolar stress and induction of apoptosis by nucleolar sequestration of NF-κB/RelA. We will also discuss the role of TIF-IA, COMMD1, and nucleophosmin, which are key players in this crosstalk, and the therapeutic relevance, particularly with respect to the antitumour effects of aspirin. Nucleoli-NF-κB-Nucleoli: An Emerging Signalling Network There are many parallels between nucleoli and the nuclear factor of κ-light-chain-enhancer of activated B cells (NF-κB) transcription factor. For example, both are stimulated by the same plethora of stresses (Table 1), both regulate the same downstream physiological processes, both are dysregulated in a variety of common diseases which contributes to disease aetiology, and both are implicated in senescence and ageing [1-6]. Until recently, it was believed that these factors act independently to regulate cellular homeostasis in health, ageing, and disease. However, there is a growing body of evidence to suggest that nucleolar stress activates the NF-κB pathway, and that nucleolar sequestration of NF-κB components is a critical apoptotic regulator. Here we will review the various levels of convergence between NF-κB and the nucleolus. We will also discuss the relevance of nucleoli-NF-κB crosstalk to the antitumour mechanisms of aspirin and the potential relevance to senescence and ageing. Highlights Nucleoli play a critical role in maintaining cellular homeostasis in health, ageing, and disease, as does the NF-κB transcription factor pathway. Emerging data suggest that interplay between these two cellular factors regulates cell growth and death. An atypical nucleolar stress response pathway, characterized by degradation of the PolI complex component, TIF-IA, and nucleolar enlargement, lies upstream of NF-κB pathway activation. Components of the NF-κB complex accumulate in nucleoli in response to stress. The presence of RelA in nucleoli triggers cytoplasmic relocation of nucleophosmin which mediates apoptosis by transporting BAX to mitochondria.

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