CIC is a critical regulator of neuronal differentiation

Hwang, Inah; Pan, Heng; Yao, Jun; Elemento, Olivier; Zheng, Hongwu; Paik, Jihye

doi:10.1172/jci.insight.135826

Cited by 27 publications

(37 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is supported by several transcriptomic studies where upregulation of polycomb repressive complex‐responsive genes has been identified in cell lines and tumours with CIC loss . In line with these observations, CIC is also able to recruit the SWI/SNF complex to the promoters of its target genes through interaction with ARID1A/B, SMARCC1/2, and SMARCA2/4 . This functional interaction with the SWI/SNF complex may be critical for the dynamic regulation of the epigenome during normal differentiation or contribute to epigenomic dysregulation in cancer.…”

Section: Functional Cic Interactorssupporting

confidence: 60%

“…However, more intriguing was that most of the differentially expressed genes in the Cic knockout did not respond to EGF; and that CIC ChIP‐seq analyses identified several loci directly bound by CIC in a large majority of downregulated genes, suggesting that CIC may have broad functions independent of MAPK, acting as both a transcriptional repressor and activator . In all of the above studies, investigating the role of Cic in neural development, loss of Cic resulted in reduced cortical thickness, decreased brain size, hyperproliferation of the sub‐ventricular zone and partial postnatal lethality . Interestingly, Cic knockout in neural progenitors using Gfap‐Cre did not result in significant alteration of brain structure or histopathology, which suggests that the window of time in which normal CIC function is critical for proper differentiation is small .…”

Section: The Role Of Cic In Normal Mammalian Development and Oncogenesismentioning

confidence: 99%

“…Although CIC interaction with ATXN1/ATXN1L may facilitate CIC stability and repression of target genes, CIC interaction with the SIN3/HDAC complex (SIN3A/B, RBBP4/7, HDAC1/2) is responsible for directly mediating the repression of CIC target genes (Figure ) . Increased H3K27 and H3K9 acetylation, both markers of active transcription, can be observed at the promoters of CIC target genes following loss of CIC or RTK/MAPK activation . Interestingly, loss of H3K27 trimethylation, a histone mark associated with transcriptional repression, has also been associated with IDH mutated 1p19q co‐deleted ODG, but not other gliomas.…”

Section: Functional Cic Interactorsmentioning

confidence: 99%

See 2 more Smart Citations

Making heads or tails – the emergence of capicua (CIC) as an important multifunctional tumour suppressor

Wong

Yip

2020

The Journal of Pathology

View full text Add to dashboard Cite

Capicua, encoded by the gene CIC, is an evolutionarily conserved high-mobility group-box transcription factor downstream of the receptor tyrosine kinase and mitogen-activated protein kinase pathways. It was initially discovered and studied in Drosophila. Recurrent mutations in CIC were first identified in oligodendroglioma, a subtype of low-grade glioma. Subsequent studies have identified CIC aberrations in multiple types of cancer and have established CIC as a potent tumour suppressor involved in regulating pathways related to cell growth and proliferation, invasion and treatment resistance. The most well-known and studied targets of mammalian CIC are the oncogenic E-Twenty Six transcription factors ETV1/4/5, which have been found to be elevated in cancers with CIC aberrations. Here, we review the role of CIC in normal mammalian development, oncogenesis and tumour progression, and the functional interactors that mediate them.

show abstract

Section: Functional Cic Interactorssupporting

confidence: 60%

Section: The Role Of Cic In Normal Mammalian Development and Oncogenesismentioning

confidence: 99%

Section: Functional Cic Interactorsmentioning

confidence: 99%

See 1 more Smart Citation

Making heads or tails – the emergence of capicua (CIC) as an important multifunctional tumour suppressor

Wong

Yip

2020

The Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Using CIC KO cell lines with stably expressing FLAG-tagged CIC-S [ 30 ], CIC interaction with 14-3-3 regulatory proteins and the nuclear pore protein TPR was observed to increase following siRNA knockdown of ATXN1L using PLA (Additional file 5 : Figure S4A, B, C). CIC was not found to interact with many previously identified proteins involved in transcriptional regulation such as SIN3A, HDAC1/2, and members of the SWI/SNF complex in our ATXN1L KO background which may contribute to the dysregulation of CIC target genes [ 30 – 32 ]. Among the most highly enriched CIC interactors was the E3-ligase TRIM25.…”

Section: Resultsmentioning

confidence: 96%

TRIM25 promotes Capicua degradation independently of ERK in the absence of ATXN1L

et al. 2020

View full text Add to dashboard Cite

Background Aberrations in Capicua (CIC) have recently been implicated as a negative prognostic factor in a multitude of cancer types through the derepression of targets downstream of the mitogen-activated protein kinase (MAPK) signaling cascade, such as oncogenic E26 transformation-specific (ETS) transcription factors. The Ataxin-family protein ATXN1L has previously been reported to interact with CIC in both developmental and disease contexts to facilitate the repression of CIC target genes and promote the post-translational stability of CIC. However, little is known about the mechanisms at the base of ATXN1L-mediated CIC post-translational stability. Results Functional in vitro studies utilizing ATXN1LKO human cell lines revealed that loss of ATXN1L leads to the accumulation of polyubiquitinated CIC protein, promoting its degradation through the proteasome. Although transcriptomic signatures of ATXN1LKO cell lines indicated upregulation of the mitogen-activated protein kinase pathway, ERK activity was found to contribute to CIC function but not stability. Degradation of CIC protein following loss of ATXN1L was instead observed to be mediated by the E3 ubiquitin ligase TRIM25 which was further validated using glioma-derived cell lines and the TCGA breast carcinoma and liver hepatocellular carcinoma cohorts. Conclusions The post-translational regulation of CIC through ATXN1L and TRIM25 independent of ERK activity suggests that the regulation of CIC stability and function is more intricate than previously appreciated and involves several independent pathways. As CIC status has become a prognostic factor in several cancer types, further knowledge into the mechanisms which govern CIC stability and function may prove useful for future therapeutic approaches.

show abstract

“…Chromatin immunoprecipitation (ChIP). ChIP analysis was performed following the previous report 67 . In brief, 3 × 10 7 cells were crosslinked for 5 min with 1% paraformaldehyde and quenched with 125 mM glycine for 5 min at room temperature.…”

Section: Discussionmentioning

confidence: 99%

Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification

et al. 2021

Self Cite

View full text Add to dashboard Cite

Neural stem/progenitor cells (NSPCs) persist over the lifespan while encountering constant challenges from age or injury related brain environmental changes like elevated oxidative stress. But how oxidative stress regulates NSPC and its neurogenic differentiation is less clear. Here we report that acutely elevated cellular oxidative stress in NSPCs modulates neurogenic differentiation through induction of Forkhead box protein O3 (FOXO3)-mediated cGAS/STING and type I interferon (IFN-I) responses. We show that oxidative stress activates FOXO3 and its transcriptional target glycine-N-methyltransferase (GNMT) whose upregulation triggers depletion of s-adenosylmethionine (SAM), a key co-substrate involved in methyl group transfer reactions. Mechanistically, we demonstrate that reduced intracellular SAM availability disrupts carboxymethylation and maturation of nuclear lamin, which induce cytosolic release of chromatin fragments and subsequent activation of the cGAS/STING-IFN-I cascade to suppress neurogenic differentiation. Together, our findings suggest the FOXO3-GNMT/SAM-lamin-cGAS/STING-IFN-I signaling cascade as a critical stress response program that regulates long-term regenerative potential.

show abstract

CIC is a critical regulator of neuronal differentiation

Cited by 27 publications

References 54 publications

Making heads or tails – the emergence of capicua (CIC) as an important multifunctional tumour suppressor

Making heads or tails – the emergence of capicua (CIC) as an important multifunctional tumour suppressor

TRIM25 promotes Capicua degradation independently of ERK in the absence of ATXN1L

Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification

Contact Info

Product

Resources

About