Mitochondrial translocation of cyclin C stimulates intrinsic apoptosis through Bax recruitment

Ježek, Jan; Chang, Kai-Ti; Joshi, Amogh; Strich, Randy

doi:10.15252/embr.201847425

Cited by 33 publications

(43 citation statements)

References 47 publications

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“…Recently, it has been shown that Cyclin C associates with Bcl-2 homology containing protein BAX and tethers it with the stress-induced mitochondrial fission complex in the mammalian cell line. This provides sufficient dwell time on mitochondria for BAX to be recognized by the BH3 containing proteins leading to initiation of PCD in the mammalian cell line [88]. Since Cyclin C translocation from the nucleus to the cytoplasm is a conserved process from the yeast to humans, this finding of TDP-43-induced Cyclin C translocation in yeast may have direct relevance to the ALS pathology [83,85,88,91,92].…”

Section: Discussionmentioning

confidence: 90%

“…Alike to the cnc1 yeast presence of functional mitochondria was also essential for the rescue in the dnm1 yeast. It is noteworthy that an inhibitor of Drp1 and Fis1 interaction was previously found to relieve the TDP-43-induced mitochondrial fragmentation and cytotoxicity [88]. Surprisingly however, the toxicity of TDP-43 was not rescued in the fis1yeast the reason for which is not completely understood.…”

Section: Discussionmentioning

confidence: 96%

“…This provides sufficient dwell time on mitochondria for BAX to be recognized by the BH3 containing proteins leading to initiation of PCD in the mammalian cell line [88]. Since Cyclin C translocation from the nucleus to the cytoplasm is a conserved process from the yeast to humans, this finding of TDP-43-induced Cyclin C translocation in yeast may have direct relevance to the ALS pathology [83,85,88,91,92]. Therefore, targeting the TDP-43 expression-induced oxidative stress and the Cyclin C translocation may have potentially fruitful consequences towards finding of the ALS therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

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Role ofCNC1gene in TDP-43 aggregation-induced oxidative stress-mediated cell death inS. cerevisiaemodel of ALS

Bharathi

Girdhar

Patel

2020

Preprint

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TDP-43 is a multi-functional ribonucleoprotein that is also found deposited as hyperphosphorylated and ubiquitinated TDP-43 inclusions in the brain and spinal cord of the patients of the motor neuron diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Till date, how the cell death ensues is not fully deciphered although several molecular mechanisms of the TDP-43 toxicity such as impairments of endocytosis and chromatin remodelling, mis-regulations of autophagy and proteasome function, mis-localization to the mitochondria and generation of oxidative stress etc., have been proposed. A predominantly nuclear protein, Cyclin C, can regulate the oxidative stress response by affecting the transcription of stress response genes and also by translocation to the cytoplasm for the activation of the mitochondrial fragmentation-dependent cell death pathway. Using the well-established yeast model of TDP-43 aggregation and toxicity, we examined here whether upon TDP-43 aggregation, the cell survival depends on the presence of the CNC1 gene that encodes Cyclin C protein or other genes that encode proteins that function in conjunction with Cyclin C, such as the DNM1, FIS1 and MED13 genes. We found that the TDP-43 toxicity is significantly reduced in the yeast deleted for the CNC1 or DNM1 genes. Importantly, the rescue of TDP-43 toxicity in these yeast deletion backgrounds required the presence of functional mitochondria. Also, the deletion of YBH3 gene, which encodes for a protein involved in the mitochondria-dependent apoptosis, also reduced the TDP-43 toxicity. Furthermore, Cyclin C-YFP was observed to localize from the nucleus to the cytoplasm in response to the TDP-43 co-expression. Also, this cytoplasmic localization of Cyclin C was prevented by the addition of an anti-oxidant molecule, N-acetyl-cysteine.Taken together, our data suggest that Cyclin C, Dnm1 and Ybh3 proteins are important in mediating the TDP-43-induced oxidative stress-mediated cell death in the S. cerevisiae model.3

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Role ofCNC1gene in TDP-43 aggregation-induced oxidative stress-mediated cell death inS. cerevisiaemodel of ALS

Bharathi

Girdhar

Patel

2020

Preprint

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“…The binding domain on cyclin C directing this interaction is termed the holoenzyme-associating domain or HAD (Cooper and Strich, 1999). We recently demonstrated that addition of a cellpenetrating stapled HAD mimetic peptide (S-HAD) induced cyclin C nuclear release in the absence of stress (Jezek et al, 2019). The finding that cyclin C is present in thyroid cancer cell lines prompted the question of whether S-HAD had a similar activity in PDTC cell line D316.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to its role in transcription, cyclin C also has a Cdk8independent role in mediating stress-induced mitochondrial fragmentation and mitochondrial outer membrane permeability (MOMP) (Ganesan et al, 2019;Wang et al, 2015), the commitment step to intrinsic mitochondrial-dependent regulated cell death type 1 (RCD-1) (Galluzzi et al, 2015). This function is highly conserved, as cyclin C is required for mitochondrial fission and stress-induced cell death in budding yeast (Cooper et al, 2014) and mammalian cells (Jezek et al, 2019). Finally, deleting cyclin C protects mouse embryonic fibroblast (MEF) cells from RCD-1 induced by oxidative stress or the anti-cancer drug cisplatin (Wang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Synergistic repression of thyroid hyperplasia by cyclin C and Pten

Ježek

Wang

Yan

et al. 2019

Journal of Cell Science

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The cyclin C-Cdk8 kinase has been identified as both a tumor suppressor and an oncogene depending on the cell type. The genomic locus encoding cyclin C (Ccnc) is often deleted in aggressive anaplastic thyroid tumors. To test for a potential tumor suppressor role for cyclin C, Ccnc alone, or Ccnc in combination with a previously described thyroid tumor suppressor Pten, was deleted late in thyroid development. Although mice harboring individual Pten or Ccnc deletions exhibited modest thyroid hyperplasia, the double mutant demonstrated dramatic thyroid expansion resulting in animal death by 22 weeks. Further analysis revealed that Ccnc thyr−/− tissues exhibited a reduction in signal transducer and activator of transcription 3 (Stat3) phosphorylation at Ser727. Further analysis uncovered a post-transcriptional requirement of both Pten and cyclin C in maintaining the levels of the p21 and p53 tumor suppressors (also known as CDKN1A and TP53, respectively) in thyroid tissue. In conclusion, these data reveal the first tumor suppressor role for cyclin C in a solid tumor model. In addition, this study uncovers new synergistic activities of Pten and cyclin C to promote quiescence through maintenance of p21 and p53.

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Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer

Jiang

Chen

et al. 2022

Clinical & Translational Med

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Background Cyclin C (CCNC) was reported to take part in regulating mitochondria‐derived oxidative stress under cisplatin stimulation. However, its effect in gastric cancer is unknown. This study aimed to investigate the role of cyclin C and its ubiquitylation in regulating cisplatin resistance in gastric cancer. Methods The interaction between HECT domain and ankyrin repeat‐containing E3 ubiquitin‐protein ligase 1 (HACE1) and cyclin C was investigated by GST pull‐down assay, co‐immunoprecipitation and ubiquitylation assay. Mitochondria‐derived oxidative stress was studied by MitoSOX Red assay, seahorse assay and mitochondrial membrane potential measurement. Cyclin C‐associated cisplatin resistance was studied in vivo via xenograft. Results HACE1 catalysed the ubiquitylation of cyclin C by adding Lys11‐linked ubiquitin chains when cyclin C translocates to cytoplasm induced by cisplatin treatment. The ubiquitin‐modified cyclin C then anchor at mitochondira, which induced mitochondrial fission and ROS synthesis. Depleting CCNC or mutation on the ubiquitylation sites decreased mitochondrial ROS production and reduced cell apoptosis under cisplatin treatment. Xenograft study showed that disrupting cyclin C ubiquitylation by HACE1 conferred impairing cell apoptosis response upon cisplatin administration. Conclusions Cyclin C is a newly identified substrate of HACE1 E3 ligase. HACE1‐mediated ubiquitylation of cyclin C sheds light on a better understanding of cisplatin‐associated resistance in gastric cancer patients. Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer. With cisplatin‐induced nuclear–mitochondrial translocation of cyclin C, its ubiquitylation by HACE1 increased mitochondrial fission and mitochondrial‐derived oxidative stress, leading to cell apoptosis.

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Mitochondrial translocation of cyclin C stimulates intrinsic apoptosis through Bax recruitment

Cited by 33 publications

References 47 publications

Role ofCNC1gene in TDP-43 aggregation-induced oxidative stress-mediated cell death inS. cerevisiaemodel of ALS

Role ofCNC1gene in TDP-43 aggregation-induced oxidative stress-mediated cell death inS. cerevisiaemodel of ALS

Synergistic repression of thyroid hyperplasia by cyclin C and Pten

Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer

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