Mitofusin-2 is a novel direct target of p53

Wang, Weilin; Cheng, Xiaofei; Lu, Jianju; Wei, Jianfeng; Fu, Guanghou; Zhu, Feng; Chen, Jia; Zhou, Lin; Xie, Haiyang; Zheng, Shusen

doi:10.1016/j.bbrc.2010.08.108

Cited by 56 publications

(43 citation statements)

References 25 publications

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“…The cyclin B/Cdk1 complex is retained in the cytosol, leading to weak Cdk1 activation and the impaired entry of cells into mitosis when ERK1/2 activity is inhibited [24]. We demonstrated previously that Mfn2 is a novel p53-inducible target gene [9]. Thus, we speculate that Mfn2 inhibits the growth of CRC cells: the role of ERK1/2,G2/M-phase cell cycle arrest and p53.…”

Section: Discussionmentioning

confidence: 79%

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Cell-cycle arrest at G2/M and proliferation inhibition by adenovirus-expressed mitofusin-2 gene in human colorectal cancer cell lines

Cheng¹,

Zhou²,

Jiang³

et al. 2014

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The mitofusin-2 (Mfn2) is a novel gene characterised as a cell proliferation inhibitor. Mfn2 protein over-expression, mediated by an adenovirus, has a significant anti-proliferative effect in hepatoma carcinoma cells. However, there is no report on the effect of Mfn2 on colorectal cancer (CRC). In this study, we found that Mfn2 protein and mRNA levels were downregulated in CRC tissues compared to nearby normal tissues. An adenovirus encoding the complete Mfn2 open reading frame (Ad-Mfn2) exhibited a prominent anti-proliferative effect in the CRC cell lines HCT 116, HT-29, and SW480. AdMfn2 infection significantly inhibited the proliferation of CRC cells compared with Ad-GFP infection. Mfn2 overexpression resulted in a cell-cycle arrest at G2/M phase in CRC cells, and it increased the levels of p-cdc2 (Tyr15) and Myt1; however, the levels of cyclin B1 and p-ERK1/2 was reduced. Mfn2 overexpression aslo increased the levels of active caspase-3 and cleaved PARP. Taken together, these findings indicate that Mfn2 has a significant anti-proliferative effect in CRC cells using adenoviral vectors.

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Section: Discussionmentioning

confidence: 79%

“…We demonstrated previously that Mfn2 is a novel p53-inducible target gene in hepatocellular carcinoma cells [9].…”

mentioning

confidence: 92%

Cell-cycle arrest at G2/M and proliferation inhibition by adenovirus-expressed mitofusin-2 gene in human colorectal cancer cell lines

Cheng¹,

Zhou²,

Jiang³

et al. 2014

neo

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“…Changes in mitochondrial morphology have been linked to apoptotic cell death (Ong and Hausenloy, 2010), and Mfn2, independent of its pro‐fusion properties, can bind with a pro‐apoptotic member of the Bcl‐2 family, Bax (Wang et al, 2010). Mfn2 is able to form a functional unit with the mitochondrial fission protein, dynamin‐related protein 1, and Bax at the outer mitochondrial membrane to mediate apoptotic cell death (Karbowski et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

McLaughlin

Zhao

O’Neill

et al. 2017

British J Pharmacology

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Background and PurposeThe anthracycline doxorubicin (DOX), although successful as a first‐line cancer treatment, induces cardiotoxicity linked with increased production of myocardial ROS, with Nox2 NADPH oxidase‐derived superoxide reported to play a key role. The aim of this study was to identify novel mechanisms underlying development of cardiac remodelling/dysfunction further to DOX‐stimulated Nox2 activation.Experimental ApproachNox2−/− and wild‐type (WT) littermate mice were administered DOX (12 mg·kg−1 over 3 weeks) prior to study at 4 weeks. Detailed mechanisms were investigated in murine HL‐1 cardiomyocytes, employing a robust model of oxidative stress, gene silencing and pharmacological tools.Key ResultsDOX‐induced cardiac dysfunction, cardiomyocyte remodelling, superoxide production and apoptosis in WT mice were attenuated in Nox2−/− mice. Transcriptional analysis of left ventricular tissue identified 152 differentially regulated genes (using adjusted P < 0.1) in DOX‐treated Nox2−/− versus WT mice, and network analysis highlighted ‘Cell death and survival’ as the biological function most significant to the dataset. The mitochondrial membrane protein, mitofusin‐2 (Mfn2), appeared as a strong candidate, with increased expression (1.5‐fold), confirmed by qPCR (1.3‐fold), matching clear published evidence of promotion of cardiomyocyte cell death. In HL‐1 cardiomyocytes, targeted siRNA knockdown of Nox2 decreased Mfn2 protein expression, but not vice versa. While inhibition of Nox2 activity along with DOX treatment attenuated its apoptotic and cytotoxic effects, reduced apoptosis after Mfn2 silencing reflected a sustained cytotoxic response and reduced cell viability.Conclusions and ImplicationsDOX‐induced and Nox2‐mediated up‐regulation of Mfn2, rather than contributing to cardiomyocyte dysfunction through apoptotic pathways, appears to promote a protective mechanism.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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“…These findings suggest the presence of cross-talk between Mfn1/2 and p53/ p21 signaling during the reprogramming process. It is already well established that Mfn2 is a direct p53-inducible target gene, 16 and that Mfn2 and Mfn1 (which shares a high degree of homology with Mfn2) directly bind Ras and Raf, resulting in the inhibition of cell proliferation via sequestration of Ras-Raf-ERK signaling. 17,18 Under our experimental conditions, we observed a dramatic increase in the levels of phosphorylated Raf, ERK, PI3K, Akt, and mTOR proteins in the reprogramming intermediates of Mfn1/2 knockdown cells on D7 of reprogramming (Figure 5e).…”

Section: Cell Cyclementioning

confidence: 99%

Mitofusins deficiency elicits mitochondrial metabolic reprogramming to pluripotency

et al. 2015

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Cell reprogramming technology has allowed the in vitro control of cell fate transition, thus allowing for the generation of highly desired cell types to recapitulate in vivo developmental processes and architectures. However, the precise molecular mechanisms underlying the reprogramming process remain to be defined. Here, we show that depleting p53 and p21, which are barriers to reprogramming, yields a high reprogramming efficiency. Deletion of these factors results in a distinct mitochondrial background with low expression of oxidative phosphorylation subunits and mitochondrial fusion proteins, including mitofusin 1 and 2 (Mfn1/2). Importantly, Mfn1/2 depletion reciprocally inhibits the p53-p21 pathway and promotes both the conversion of somatic cells to a pluripotent state and the maintenance of pluripotency. Mfn1/2 depletion facilitates the glycolytic metabolic transition through the activation of the Ras-Raf and hypoxia-inducible factor 1α (HIF1α) signaling at an early stage of reprogramming. HIF1α is required for increased glycolysis and reprogramming by Mfn1/2 depletion. Taken together, these results demonstrate that Mfn1/2 constitutes a new barrier to reprogramming, and that Mfn1/2 ablation facilitates the induction of pluripotency through the restructuring of mitochondrial dynamics and bioenergetics. Cell Death and Differentiation (2015) 22, 1957-1969 doi:10.1038/cdd.2015; published online 17 April 2015Cell fate transition occurs under various developmental, physiological, and pathological conditions, including normal embryonic development, aging, and tissue regeneration, as well as tumor initiation and progression. Defining the cellular and molecular mechanisms of cell fate transition and learning to control these mechanisms may be essential for treating abnormal pathological conditions resulting from improper regulation of cell fate. The recent development of induced pluripotent stem cell (iPSC) technology has allowed for the reprogramming of somatic cells to pluripotent stem cells through the use of defined pluripotency factors, and has allowed us to more closely mimic and recapitulate the conditions of cell fate transitions.1 In studying aspects of somatic cell reprogramming related to pluripotency, dramatic and complex molecular changes at the genetic, epigenetic, and metabolic levels have been observed during the initial stage of reprogramming.2 Cell reprogramming faces the challenge of balancing stability and plasticity and must overcome critical barriers, such as cell cycle checkpoints, the mesenchymal-epithelial transition, and metabolic reprogramming, to progress cell fate conversion from a stochastic early phase toward pluripotency. 3The p53 pathway limits cell fate transition by inducing classical signaling that leads to cell cycle arrest, senescence, or apoptosis to maintain genome stability in the face of reprogramming-induced stress. Thus, compromising p53 signaling accelerates the reprogramming process.4-6 Recent reports have provided data showing that the fast-cycling population is enric...

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Mitofusin-2 is a novel direct target of p53

Cited by 56 publications

References 25 publications

Cell-cycle arrest at G2/M and proliferation inhibition by adenovirus-expressed mitofusin-2 gene in human colorectal cancer cell lines

Cell-cycle arrest at G2/M and proliferation inhibition by adenovirus-expressed mitofusin-2 gene in human colorectal cancer cell lines

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

Mitofusins deficiency elicits mitochondrial metabolic reprogramming to pluripotency

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