Regulation of monocyte induced cell migration by the RNA binding protein, FXR1

Tonquèze, Olivier Le; Kollu, Swapna; Lee, S; Al-Salah, M; Truesdell, Samuel S.; Vasudevan, Shobha

doi:10.1080/15384101.2016.1189040

Cited by 21 publications

(26 citation statements)

References 43 publications

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“…STAT is well established in regulating cytokine gene transcription. We have also observed that FXR1 knockdown inhibited the expression of multiple cytokines (data not shown), consistent with a recent report of FXR1 function in positively regulating cytokine expression in monocytes ( Le Tonqueze et al, 2016 ). Notably, only about 0.7–1.57% of the STAT1/3 peaks overlap with FXR1 peaks in our ChIP-seq study, suggesting that FXR1 only participates in the transcription of a very small fraction of JAK-STAT target genes.…”

Section: Discussionsupporting

confidence: 92%

FXR1 regulates transcription and is required for growth of human cancer cells with TP53/FXR2 homozygous deletion

Fan

Jiao

Xiao

et al. 2017

eLife

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Tumor suppressor p53 prevents cell transformation by inducing apoptosis and other responses. Homozygous TP53 deletion occurs in various types of human cancers for which no therapeutic strategies have yet been reported. TCGA database analysis shows that the TP53 homozygous deletion locus mostly exhibits co-deletion of the neighboring gene FXR2, which belongs to the Fragile X gene family. Here, we demonstrate that inhibition of the remaining family member FXR1 selectively blocks cell proliferation in human cancer cells containing homozygous deletion of both TP53 and FXR2 in a collateral lethality manner. Mechanistically, in addition to its RNA-binding function, FXR1 recruits transcription factor STAT1 or STAT3 to gene promoters at the chromatin interface and regulates transcription thus, at least partially, mediating cell proliferation. Our study anticipates that inhibition of FXR1 is a potential therapeutic approach to targeting human cancers harboring TP53 homozygous deletion.

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Section: Discussionsupporting

confidence: 92%

FXR1 regulates transcription and is required for growth of human cancer cells with TP53/FXR2 homozygous deletion

Fan

Jiao

Xiao

et al. 2017

eLife

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“…However, TP53 is frequently mutated in the disease, allowing tumour cells to escape cell cycle arrest and continue proliferating , which can also lead to increased resistance to chemo‐ and radiotherapy . FXR1 may support this evasion of arrest through negative regulation and/or destabilisation of p21 and stabilisation of telomerase RNA component (TERC) activity in vitro .…”

Section: Identification Of Pro‐oncogenic Factors In 3q26‐29mentioning

confidence: 99%

“…This is exemplified by the recent approval of pembrolizumab. FXR1 may have a putative role in the innate immune response through positive regulation of the proinflammatory cytokines C‐C motif‐chemokine ligand 2 (CCL2) and interleukin 1 beta (IL1β) in monocytes . CCL2 mRNA is significantly upregulated in HNSCC compared to normal human keratinocytes and is secreted by HNSCC tumour cells to recruit peripheral monocytes and macrophages.…”

Section: Identification Of Pro‐oncogenic Factors In 3q26‐29mentioning

confidence: 99%

3q26‐29 Amplification in head and neck squamous cell carcinoma: a review of established and prospective oncogenes

Davidson

Shanks

2017

The FEBS Journal

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Head and neck squamous cell carcinoma (HNSCC) is significantly underrepresented in worldwide cancer research, yet survival rates for the disease have remained static for over 50 years. Distant metastasis is often present at the time of diagnosis, and is the primary cause of death in cancer patients. In the absence of routine effective targeted therapies, the standard of care treatment remains chemoradiation in combination with (often disfiguring) surgery. A defining characteristic of HNSCC is the amplification of a region of chromosome 3 (3q26‐29), which is consistently associated with poorer patient outcome. This review provides an overview of the role the 3q26‐29 region plays in HNSCC, in terms of both known and as yet undiscovered processes, which may have potential clinical relevance.

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“…Taking into consideration the fact that FXR1 forms SDS-resistant conformers and strongly colocalizes with Thioflavin S, we can conclude that this protein is present in rat brain in amyloid form under native conditions. It is known that FXR1 binds to different RNA molecules that form secondary structures and affects their level and translation efficiency (25). We suggested that amyloid conformers of FXR1 may protect RNA from action of ribonucleases that normally present in eukaryotic cells and take part in a gene expression control.…”

Section: Fxr1 Forms Functional Amyloid Conformers In Brain That Bind mentioning

confidence: 97%

Amyloid conformers of the FXR1 protein prevent mRNA degradation in cortical neurons

Sopova¹,

Koshel²,

Zadorsky³

et al. 2019

Preprint

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Functional amyloids regulate vital processes in a variety of organisms from bacteria to higher eukaryotes. The development of methods enabling large-scale screening for amyloids opens up opportunity for systemic analysis of the prevalence of amyloids in nature. Using an original proteomic approach, we identified several proteins forming amyloid-like detergent-resistant aggregates in the rat brain. One of them is the FXR1 protein, which is known to regulate memory and emotions (1,2). We demonstrated that in brain FXR1 forms amyloid oligomers and insoluble detergent-resistant aggregates that strongly colocalize with amyloid-specific dye Thioflavin S and bind mRNA molecules. Moreover, we demonstrated that mRNAs colocalized with FXR1 amyloid particles are completely resistant to treatment with RNAse A. Taking into consideration that the members of ribonuclease A superfamily function in neurons (3) we can conclude that amyloid conformers of FXR1 control RNA stability in brain. Thus, in contrast to pathological amyloids that cause neurodegeneration, FXR1 is the functional amyloid in forebrain. We showed that amyloid properties of FXR1 depend on its N-terminal part from 1 to 379 amino acids. This fragment forms amyloid fibrils in vitro that bind Congo red and manifest apple-green birefringence when assayed by polarization microscopy. The amyloid-forming region of FXR1 is highly conserved in mammals. These data suggest that the ability of amyloid conformers of FXR1 to protect mRNAs is characteristic of different mammalian species, including humans. Significance StatementAmyloids are highly ordered cross-β sheet protein fibrils associated with many neurodegenerative diseases including Alzheimer's disease. However, some amyloid proteins regulate vital processes. We identified a set of proteins that form amyloid-like aggregates in the brain of healthy rats. One of them -the FXR1 protein is known to regulate memory and emotions. FXR1 forms amyloid fibrils that bind RNA molecules and prevent their degradation in brain cortex neurons. Amyloid-forming sequence of FXR1 is highly conserved across mammals including human. Discovery of functional amyloids in mammalian brain shows that strategy aimed at the development of universal anti-amyloid drugs is unpromising. Such potential drugs should prevent or suppress formation of pathological aggregates of a certain protein, but not affect functional amyloids.

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Regulation of monocyte induced cell migration by the RNA binding protein, FXR1

Cited by 21 publications

References 43 publications

FXR1 regulates transcription and is required for growth of human cancer cells with TP53/FXR2 homozygous deletion

FXR1 regulates transcription and is required for growth of human cancer cells with TP53/FXR2 homozygous deletion

3q26‐29 Amplification in head and neck squamous cell carcinoma: a review of established and prospective oncogenes

Amyloid conformers of the FXR1 protein prevent mRNA degradation in cortical neurons

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