Regulation of Bcl-xL-ATP Synthase Interaction by Mitochondrial Cyclin B1-Cyclin-Dependent Kinase-1 Determines Neuronal Survival

Tudela, Miguel Veas-Pérez de; Delgado‐Esteban, María; Maestre, Carolina; Bobo-Jiménez, Verónica; Jiménez-Blasco, Daniel; Vecino, Rebeca; Bolaños, Juan P.; Almeida, Ángeles

doi:10.1523/jneurosci.4712-14.2015

Cited by 43 publications

(55 citation statements)

References 55 publications

(38 reference statements)

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“…Also, Cdk1-CycB complex is activated in the cytoplasm before its nuclear activation in mammalian cultured cells [14]. The expression of Cdk1 and CyclinB1 is higher in cytoplasm and mitochondria than in nucleus via subcellular fractionation in neurons and HEK293T cells [24]. When all is said and done, we imply that cytoplasmic Cdk1 expressed in ovarian cancer can be activated and this altered expression of cytoplasmic Cdk1 might influence in ovarian cancer growth.…”

Section: Discussionmentioning

confidence: 99%

Accumulation of cytoplasmic Cdk1 is associated with cancer growth and survival rate in epithelial ovarian cancer

et al. 2016

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Cyclin dependent kinase 1 (Cdk1) have previously reported correlation with cancer growth and a key regulator for cell cycle. Mostly, Cdk1′s function of nucleus for cell cycle is well known to be associated with cancer, but cytoplasmic Cdk1′s traits are not clearly identified, yet. We revealed that tissue microarray blocks of epithelial ovarian cancer (n = 249) showed increased level of cytoplasmic Cdk1 (p < 0.001), but not in nucleus (p = 0.192) of histologic cell type independently. On survival analysis, Cdk1 overexpression conferred a significantly worse prognosis in 5-year overall survival (Log-rank p = 0.028, Hazard ratio = 2.016, 95% CI = 1.097 to 4.635). Also, the expression of Cdk1 was increased in ovarian cancer cell lines and Gene Expression Omnibus datasets. When the expression and activity of Cdk1 were inhibited by si-Cdk1 or RO-3306 which is a potent Cdk1 inhibitor, the growth of ovarian cancer was diminished. Moreover, combined treatment with RO-3306 and cisplatin in ovarian cancer significantly elevated anti-cancer effects than single-agent treatment. In conclusion, cytoplasmic Cdk1 expression which was elevated in ovarian cancer predicts a poor overall survival. The inhibition of Cdk1 expression and activity reduced ovarian cancer growth.

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Section: Discussionmentioning

confidence: 99%

Accumulation of cytoplasmic Cdk1 is associated with cancer growth and survival rate in epithelial ovarian cancer

et al. 2016

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“…It has been shown that okadaic acid induced cyclin B1 expression and mitotic catastrophe in rat cortex [34]. Cyclin B1 was accumulated and mediated excitotoxicity in neurons [31,35]. In our previous study, we found that high glucose induced cyclin B1 expression in neurons [11].…”

Section: Discussionmentioning

confidence: 84%

“…It has been shown that continuous degradation of cyclin B1, one substrate of anaphase-promoting complex (APC), is important for survival of neurons [31]. APC, which ubiquitinates and degrades distinct quantitative oscillations of a subset of cell cycle proteins, controls the mammalian cell cycle [32].…”

Section: Discussionmentioning

confidence: 99%

Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B

Meng

Chu

Yang

et al. 2016

Cell Physiol Biochem

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Background/Aims: Metformin, the common medication for type II diabetes, has protective effects on cerebral ischemia. However, the molecular mechanisms are far from clear. Mitotic arrest deficient 2-like protein 2 (MAD2B), an inhibitor of the anaphase-promoting complex (APC), is widely expressed in hippocampal and cortical neurons and plays an important role in mediating high glucose-induced neurotoxicity. The present study investigated whether metformin modifies the expression of MAD2B and to exert its neuroprotective effects in primary cultured cortical neurons during oxygen-glucose deprivation/reoxygenation (OGD/R), a widely used in vitro model of ischemia/reperfusion. Methods: Primary cortical neurons were cultured, deprived of oxygen-glucose for 1 h, and then recovered with oxygen-glucose for 12 h and 24 h. Cell viability was measured by detecting the levels of lactate dehydrogenase (LDH) in culture medium. The levels of MAD2B, cyclin B and p-histone 3 were measured by Western blot. Results: Cell viability of neurons was reduced under oxygen-glucose deprivation/reoxygenation (OGD/R). The expression of MAD2B was increased under OGD/R. The levels of cyclin B1, which is a substrate of APC, were also increased. Moreover, OGD/R up-regulated the phosphorylation levels of histone 3, which is the induction of aberrant re-entry of post-mitotic neurons. However, pretreatment of neurons with metformin alleviated OGD/R-induced injury. Metformin further decreased the expression of MAD2B, cyclin B1 and phosphorylation levels of histone 3. Conclusion: Metformin exerts its neuroprotective effect through regulating the expression of MAD2B in neurons under OGD/R.

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“…It would therefore be important to analyze in detail the impact of X expression on mitochondria/cytosol and mitochondria/nucleus crosstalk. For instance, it was recently shown that the cyclin B1/Cdk1 complex could be actively imported within mitochondria to mediate antiapoptotic functions through phosphorylation of P53 (51) and regulation of ATP‐synthase activity (52). Thus, a better characterization of X binding partners in mitochondria and in the nucleus will undoubtedly be one of the keys to understand the X‐mediated impact on mitochondrial physiology.…”

Section: Discussionmentioning

confidence: 99%

Manipulation of the N‐terminal sequence of the Borna disease virus X protein improves its mitochondrial targeting and neuroprotective potential

et al. 2015

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To favor their replication, viruses express proteins that target diverse mammalian cellular pathways. Due to the limited size of many viral genomes, such proteins are endowed with multiple functions, which require targeting to different subcellular compartments. One salient example is the X protein of Borna disease virus, which is expressed both at the mitochondria and in the nucleus. Moreover, we recently demonstrated that mitochondrial X protein is neuroprotective. In this study, we sought to examine the mechanisms whereby the X protein transits between subcellular compartments and to define its localization signals, to enhance its mitochondrial accumulation and thus, potentially, its neuroprotective activity. We transfected plasmids expressing fusion proteins bearing different domains of X fused to enhanced green fluorescent protein (eGFP) and compared their subcellular localization to that of eGFP. We observed that the 5-16 domain of X was responsible for both nuclear export and mitochondrial targeting and identified critical residues for mitochondrial localization. We next took advantage of these findings and constructed mutant X proteins that were targeted only to the mitochondria. Such mutants exhibited enhanced neuroprotective properties in compartmented cultures of neurons grown in microfluidic chambers, thereby confirming the parallel between mitochondrial accumulation of the X protein and its neuroprotective potential.-Ferré C. A., Davezac, N., Thouard, A., Peyrin, J. M., Belenguer, P., Miquel, M.-C., Gonzalez-Dunia, D., Szelechowski, M. Manipulation of the N-terminal sequence of the Borna disease virus X protein improves its mitochondrial targeting and neuroprotective potential.

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Regulation of Bcl-xL-ATP Synthase Interaction by Mitochondrial Cyclin B1-Cyclin-Dependent Kinase-1 Determines Neuronal Survival

Cited by 43 publications

References 55 publications

Accumulation of cytoplasmic Cdk1 is associated with cancer growth and survival rate in epithelial ovarian cancer

Accumulation of cytoplasmic Cdk1 is associated with cancer growth and survival rate in epithelial ovarian cancer

Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B

Manipulation of the N‐terminal sequence of the Borna disease virus X protein improves its mitochondrial targeting and neuroprotective potential

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