Peripheral benzodiazepine receptor regulates vascular endothelial activations via suppression of the voltage‐dependent anion channel‐1

Joo, Hee Kyoung; Lee, Yu Ran; Lim, Seongyop; Lee, Eun Ji; Choi, Sunga; Cho, Eun Jung; Park, Myoung Soo; Ryoo, Sungwoo; Park, Jin Bong; Jeon, Byeong Hwa

doi:10.1016/j.febslet.2012.03.049

Cited by 35 publications

(36 citation statements)

References 32 publications

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“…In addition, the reported grouping of TSPO molecules around VDAC, potentially reflecting TSPO polymerization [296,348], could enhance the concentration of ROS generated by TSPO in the proximity of VDAC, leading to apoptosis induction [296,349,350]. In addition, over-expression of TSPO inhibits VDAC1 expression, while the silencing of TSPO increases VDAC1 expression in endothelial cells [351]. PTP opening is regulated by different TSPO ligands, such as the agonist Ro5-4864 and the antagonist PK11195, as well as by the endogenous ligand protoporphyrin IX [352,353].…”

Section: Translocator Protein (Tspo) and Vdac1mentioning

confidence: 99%

The mitochondrial voltage-dependent anion channel 1 in tumor cells

Shoshan‐Barmatz

Ben-Hail

Admoni

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

214

254

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VDAC1 is found at the crossroads of metabolic and survival pathways. VDAC1 controls metabolic cross-talk between mitochondria and the rest of the cell by allowing the influx and efflux of metabolites, ions, nucleotides, Ca2+ and more. The location of VDAC1 at the outer mitochondrial membrane also enables its interaction with proteins that mediate and regulate the integration of mitochondrial functions with cellular activities. As a transporter of metabolites, VDAC1 contributes to the metabolic phenotype of cancer cells. Indeed, this protein is over-expressed in many cancer types, and silencing of VDAC1 expression induces an inhibition of tumor development. At the same time, along with regulating cellular energy production and metabolism, VDAC1 is involved in the process of mitochondria-mediated apoptosis by mediating the release of apoptotic proteins and interacting with anti-apoptotic proteins. The engagement of VDAC1 in the release of apoptotic proteins located in the inter-membranal space involves VDAC1 oligomerization that mediates the release of cytochrome c and AIF to the cytosol, subsequently leading to apoptotic cell death. Apoptosis can also be regulated by VDAC1, serving as an anchor point for mitochondria-interacting proteins, such as hexokinase (HK), Bcl2 and Bcl-xL, some of which are also highly expressed in many cancers. By binding to VDAC1, HK provides both a metabolic benefit and apoptosis-suppressive capacity that offer the cell a proliferative advantage and increase its resistance to chemotherapy. Thus, these and other functions point to VDAC1 as an excellent target for impairing the re-programed metabolism of cancer cells and their ability to evade apoptosis. Here, we review current evidence pointing to the function of VDAC1 in cell life and death, and highlight these functions in relation to both cancer development and therapy. In addressing the recently solved 3D structures of VDAC1, this review will point to structure-function relationships of VDAC as critical for deciphering how this channel can perform such a variety of roles, all of which are important for cell life and death. Finally, this review will also provide insight into VDAC function in Ca2+ homeostasis, protection against oxidative stress, regulation of apoptosis and involvement in several diseases, as well as its role in the action of different drugs. We will discuss the use of VDAC1-based strategies to attack the altered metabolism and apoptosis of cancer cells. These strategies include specific siRNA able to impair energy and metabolic homeostasis, leading to arrested cancer cell growth and tumor development, as well VDAC1-based peptides that interact with anti-apoptotic proteins to induce apoptosis, thereby overcoming the resistance of cancer cell to chemotherapy. Finally, small molecules targeting VDAC1 can induce apoptosis. VDAC1 can thus be considered as standing at the crossroads between mitochondrial metabolite transport and apoptosis and hence represents an emerging cancer drug target. This article is part of a Special ...

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Section: Translocator Protein (Tspo) and Vdac1mentioning

confidence: 99%

The mitochondrial voltage-dependent anion channel 1 in tumor cells

Shoshan‐Barmatz

Ben-Hail

Admoni

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

214

254

View full text Add to dashboard Cite

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“…In addition, mammalian TSPOs can regulate the expression or stability of their interacting partner. For instance, overexpression of TSPO1 inhibits the expression of the mitochondrial voltage-dependent anion channel 1 (VDAC1), and the silencing of TSPO1 increases VDAC1 expression in endothelial cells (Joo et al, 2012). Mammalian TSPO can also regulate the expression of a noninteracting protein.…”

Section: Introductionmentioning

confidence: 99%

The Arabidopsis Abiotic Stress-Induced TSPO-Related Protein Reduces Cell-Surface Expression of the Aquaporin PIP2;7 through Protein-Protein Interactions and Autophagic Degradation

et al. 2014

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The Arabidopsis thaliana multi-stress regulator TSPO is transiently induced by abiotic stresses. The final destination of this polytopic membrane protein is the Golgi apparatus, where its accumulation is strictly regulated, and TSPO is downregulated through a selective autophagic pathway. TSPO-related proteins regulate the physiology of the cell by generating functional protein complexes. A split-ubiquitin screen for potential TSPO interacting partners uncovered a plasma membrane aquaporin, PIP2;7. Pull-down assays and fluorescence imaging approaches revealed that TSPO physically interacts with PIP2;7 at the endoplasmic reticulum and Golgi membranes in planta. Intriguingly, constitutive expression of fluorescently tagged PIP2;7 in TSPO-overexpressing transgenic lines resulted in patchy distribution of the fluorescence, reminiscent of the pattern of constitutively expressed yellow fluorescent protein-TSPO in Arabidopsis. Mutational stabilization of TSPO or pharmacological inhibition of the autophagic pathway affected concomitantly the detected levels of PIP2;7, suggesting that the complex containing both proteins is degraded through the autophagic pathway. Coexpression of TSPO and PIP2;7 resulted in decreased levels of PIP2;7 in the plasma membrane and abolished the membrane water permeability mediated by transgenic PIP2;7. Taken together, these data support a physiological role for TSPO in regulating the cell-surface expression of PIP2;7 during abiotic stress conditions through protein-protein interaction and demonstrate an aquaporin regulatory mechanism involving TSPO. INTRODUCTIONEnvironmental stresses such as drought, salinity, or cold are common limiting factors for plant growth and development. These stresses impose osmotic and oxidative stresses at the cellular level, and a critical function of the phytohormone abscisic acid (ABA) is to mediate the plant response to these insults during vegetative growth (Finkelstein et al., 2002;Nambara and Marion-Poll, 2005;Yamaguchi-Shinozaki and Shinozaki, 2006). The increase in active ABA levels in plant cells during water-related stress regulates the expression of ABA-responsive genes by interacting with cytosolic and/or organelle-bound receptors and downstream effectors modulating the activity of defined transcriptional regulators (Fujii and Zhu, 2009;Ma et al., 2009;Park et al., 2009;Wu et al., 2009;Shang et al., 2010). It is thought that up to 10% of the Arabidopsis thaliana transcriptome is responsive to ABA signaling . Extensive studies of stress and ABA-induced gene expression during vegetative growth revealed two waves of response: an early transient response peaking at ;3 h and a late sustained response from 10 h onward (reviewed in Finkelstein, 2013). Characteristically, the so-called "early" genes encode regulatory proteins, such as transcription factors, protein kinases, and phosphatases, and a set of proteins of unknown function Fujita et al., 2006). The "late" genes are presumed to contribute to plant adaptation to the stress and encode proteins such as ...

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“…It was demonstrated that TSPO overexpression in cells induces mitochondrial ROS production, with a reverse trend observed after TSPO knockdown (Gatliff et al 2014). However, there exists contrasting evidence that TSPO overexpression could dampen mitochondrial ROS production through an identical VDAC-dependent mechanism (Joo et al 2012(Joo et al , 2015. Second, without the need for any protein interactions, it has been suggested …”

Section: Tspo As a Regulator Of Redox Homeostasismentioning

confidence: 99%

“…Therefore, it is possible that these interpretations may be confounded with cellular effects associated with the obvious link between stress and ROS production. The TSPO-VDAC relationship to ROS production has had contrasting results in similar TSPO overexpression studies (Gatliff et al 2014, Joo et al 2012. The TSPO-NOX2 association (Guilarte et al 2016), remains a hypothesis.…”

Section: :1mentioning

confidence: 99%

“…It has been suggested that TSPO could interact with VDAC1 or NOX2 to induce production of ROS (Gatliff et al 2014, Guilarte et al 2016. On the contrary, the association of TSPO with VDAC1 (Joo et al 2012, Joo et al 2015, or TSPO by itself (Guo et al 2015), could facilitate ROS neutralization. Although TSPO regulation of ROS is conceivable, at least as a secondary effect, functional evidence for the interactions and specific role of TSPO remains to be demonstrated.…”

Section: Tspo As An Enzyme For Protoporphyrin IX Degradationmentioning

confidence: 99%

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Current status and future perspectives: TSPO in steroid neuroendocrinology

Selvaraj

2016

Journal of Endocrinology

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The mitochondrial translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), has received significant attention both as a diagnostic biomarker and as a therapeutic target for different neuronal disease pathologies. Recently, its functional basis believed to be mediating mitochondrial cholesterol import for steroid hormone production has been refuted by studies examining both in vivo and in vitro genetic Tspo-deficient models. As a result, there now exists a fundamental gap in the understanding of TSPO function in the nervous system, and its putative pharmacology in neurosteroid production. In this review, we discuss several recent findings in steroidogenic cells that are in direct contradiction to previous studies, and necessitate a re-examination of the purported role for TSPO in de novo neurosteroid biosynthesis. We critically examine the pharmacological effects of different TSPObinding drugs with particular focus on studies that measure neurosteroid levels. We highlight the basis of key misconceptions regarding TSPO that continue to pervade the literature, and the need for interpretation with caution to avoid negative impacts. We also summarize the emerging perspectives that point to new directions that need to be investigated for understanding the molecular function of TSPO, only after which the true potential of this therapeutic target in medicine may be realized.

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Peripheral benzodiazepine receptor regulates vascular endothelial activations via suppression of the voltage‐dependent anion channel‐1

Cited by 35 publications

References 32 publications

The mitochondrial voltage-dependent anion channel 1 in tumor cells

The mitochondrial voltage-dependent anion channel 1 in tumor cells

The Arabidopsis Abiotic Stress-Induced TSPO-Related Protein Reduces Cell-Surface Expression of the Aquaporin PIP2;7 through Protein-Protein Interactions and Autophagic Degradation

Current status and future perspectives: TSPO in steroid neuroendocrinology

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