A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation

Moncunill-Massaguer, Cristina; Saura-Esteller, José; Pérez-Perarnau, Alba; Palmeri, Claudia Mariela; Núñez-Vázquez, Sonia; Cosialls, Ana M.; González-Gironès, Diana M.; Pomares, Helena; Korwitz, Anne; Preciado, Sara; Alberício, Fernando; Lavilla, Rodolfo; Pons, Gabriel; Langer, Thomas; Iglesias-Serret, Daniel; Gil, Joan

doi:10.18632/oncotarget.6154

Cited by 30 publications

(51 citation statements)

References 86 publications

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“…PHB2, also known as repressor of estrogen receptor activity, was shown to directly interact with and inhibit the transcriptional activity of the estrogen receptor [ 2 ]. Moreover, previous studies have shown that phytochemical flavaglines and the synthetic fluorinated small molecule fluorizoline target prohibitins causing disruption of the Raf-MEK-ERK signaling pathway and induction of apoptosis, respectively [ 21 – 23 ]. Taken together, the array of prohibitin activity suggests these proteins might be attractive therapeutic targets for a variety of disease states, including inflammation, obesity and cancer, however a better understanding of their cell dependent function appears to be essential [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

The prohibitin protein complex promotes mitochondrial stabilization and cell survival in hematologic malignancies

et al. 2017

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Prohibitins (PHB1 and PHB2) have been proposed to play important roles in cancer development and progression, however their oncogenic mechanism of action has not been fully elucidated. Previously, we showed that the PHB1 and PHB2 protein complex is required for mitochondrial homeostasis and survival of normal human lymphocytes. In this study, novel evidence is provided that indicates mitochondrial prohibitins are overexpressed in hematologic tumor cells and promote cell survival under conditions of oxidative stress. Immunofluorescent confocal microscopy revealed both proteins to be primarily confined to mitochondria in primary patient lymphoid and myeloid tumor cells and tumor cell lines, including Kit225 cells. Subsequently, siRNA-mediated knockdown of PHB1 and PHB2 in Kit225 cells significantly enhanced sensitivity to H2O2-induced cell death, suggesting a protective or anti-apoptotic function in hematologic malignancies. Indeed, PHB1 and PHB2 protein levels were significantly higher in tumor cells isolated from leukemia and lymphoma patients compared to PBMCs from healthy donors. These findings suggest that PHB1 and PHB2 are upregulated during tumorigenesis to maintain mitochondrial integrity and therefore may serve as novel biomarkers and molecular targets for therapeutic intervention in certain types of hematologic malignancies.

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Section: Introductionmentioning

confidence: 99%

The prohibitin protein complex promotes mitochondrial stabilization and cell survival in hematologic malignancies

et al. 2017

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“…PHB complexes are produced through interactions in the N-terminal hydrophobic region on the mitochondrial inner membrane [16, 17]. In mitochondria, PHB was also associated with mitophagy, stabilizing mitochondria genome through TFAM (Transcription Factor A, Mitochondrial), ROS (Reactive Oxygen Free Radical) reduction, mitochondrial morphology and mitochondrial apoptosis [18–22]. The function of PHB during spermatogenesis has been reported in many species, including Rattus norvegicus [23], Saccharomyces cerevisiae [24], Caenorhabditis elegans [25], Procambarus clarkii [26], Cynops orientalis [27], and Boleophthalmus pectinirostris [28].…”

Section: Introductionmentioning

confidence: 99%

Prohibitin-mediated mitochondrial ubiquitination during spermiogenesis in Chinese mitten crab Eriocheir sinensis

Hou

Wei

et al. 2017

Oncotarget

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The sperm of Eriocheir sinensis has a cup-shaped nucleus that contains several mitochondria embedded at the opening of the cup. The acrosome vesicle also contains derivants of mitochondria. The mitochondria distribution pattern involves a decrease in the number and changes in the structure and transportation of these organelles. The decreased number of sperm mitochondria is achieved through autophagy or the ubiquitination pathway. Prohibitin (PHB), the mitochondria inner membrane protein, is an evolutionarily highly conserved protein, is closely associated with spermatogenesis and sperm quality control and is also a potential substrate of ubiquitination. However, whether PHB protein mediates the ubiquitination pathway of sperm mitochondria in crustacean animals remains poorly understood. In the present study, we revealed that PHB, a substrate of ubiquitin, participates in the ubiquitination and degradation of mitochondria during spermiogenesis in E. sinensis. To confirm this finding, we used shRNA interference to reduce PHB expression and an overexpression technique to increase PHB expression in vitro. The interference experiment showed that the reduced PHB expression directly affected the polyubiquitination level and mitochondria status, whereas PHB overexpression markedly increased the polyubiquitination level. In vitro experiments also showed that PHB and its ubiquitination decide the fate of mitochondria.

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“…Phb2 is reported to localise to multiple cellular compartments (Mishra et al, 2006) and to function both in mitochondria and nucleus (Guan et al, 2014;Halevy et al, 1995;Massaguer;Merkwirth et al, 2008;Moncunill-massaguer et al, 2015;Montano et al, 1999;Wei et al, 2017). We evaluated the intracellular localisation of Phb2 in MB and MT by coimmunostaining Phb2 with markers of mitochondria (Cytochrome c -Cyc), cis-Golgi, (Golgi Matrix Protein of 130 kDa-GM130) or endoplasmic reticulum (Calreticulin-CALR) ( Fig.…”

Section: Mdia1 and Phb2 Co-localise In Cytoplasmic Punctae During Difmentioning

confidence: 99%

Cytoplasmic sequestration of the RhoA effector mDiaphanous1 by Prohibitin2 promotes muscle differentiation

Dhawan

Saleh

Subramaniam

et al. 2018

Preprint

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Running title: Phb2 interacts with mDia1 in myotubesSummary statement: mDia1 has common and stage-specific functions in muscle cells. In myotubes, mDia1 is sequestered by an interacting protein Prohibitin2, which promotes Myogenin expression and mitigates mDia1's inhibitory effects on differentiation. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/283044 doi: bioRxiv preprint first posted online Mar. 15, 2018; 2 Abstract Adhesion and growth factor dependent signalling control muscle gene expression through common effectors, coupling cytoskeletal dynamics to transcriptional activation.Earlier, we showed that mDiaphanous1, an effector of adhesion-dependent RhoA-signalling promotes MyoD expression in myoblasts, linking contractility to lineage determination. Here, we report that paradoxically, mDia1 negatively regulates MyoD function in myotubes.Knockdown of endogenous mDia1 during differentiation enhances MyoD and Myogenin expression, while over-expression of mDia1ΔN3, a RhoA-independent mutant, suppresses Myogenin promoter activity and expression. We investigated mechanisms that may counteract mDia1 to promote Myogenin expression and timely differentiation by analysing mDia1-interacting proteins. We report that mDia1 has a stage-specific interactome, including Prohibitin2, MyoD, Akt2, and β-Catenin, of which Prohibitin2 colocalises with mDia1 in cytoplasmic punctae and opposes mDia1 function in myotubes. Co-expression of mDia1-binding domains of Prohibitin2 reverses the anti-myogenic effects of mDia1ΔN3. Our results suggest that Prohibitin2 sequesters mDiaphanous1 to dampen its activity and finetune RhoAmDiaphanous1 signalling to promote differentiation. Overall, we report that mDia1 is multifunctional signaling effector with opposing functions in different cellular stages, but is modulated by a differentiation-dependent interactome.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation

Cited by 30 publications

References 86 publications

The prohibitin protein complex promotes mitochondrial stabilization and cell survival in hematologic malignancies

The prohibitin protein complex promotes mitochondrial stabilization and cell survival in hematologic malignancies

Prohibitin-mediated mitochondrial ubiquitination during spermiogenesis in Chinese mitten crab Eriocheir sinensis

Cytoplasmic sequestration of the RhoA effector mDiaphanous1 by Prohibitin2 promotes muscle differentiation

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