Hormonal Regulation of Peripheral Benzodiazepine Receptor Binding Properties Is Mediated by Subunit Interaction

Golani, Idit; Weizman, Abraham; Leschiner, Svetlana; Spanier, Ilana; Eckstein, Nachman; Limor, Rona; Yanai, Joseph; Maaser, Kerstin; Scherübl, Hans; Weisinger, Gary; Gavish, Moshe

doi:10.1021/bi010431+

Cited by 45 publications

(40 citation statements)

References 52 publications

(85 reference statements)

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“…VDAC1 levels were reduced following 2-h treatment with hCG. It has been shown that the ratio of TSPO to VDAC and ANT can be modulated by hormone treatments (48). However, the significance of this finding in steroidogenesis remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Protein-Protein Interactions Mediate Mitochondrial Cholesterol Transport and Steroid Biosynthesis

Rone

Papadopoulos

2006

Journal of Biological Chemistry

217

179

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Transport of cholesterol into the mitochondria is the ratedetermining, hormone-sensitive step in steroid biosynthesis. Here we report that the mechanism underlying mitochondrial cholesterol transport involves the formation of a macromolecular signaling complex composed of the outer mitochondrial membrane translocator protein (TSPO), previously known as peripheral-type benzodiazepine receptor; the TSPO-associated protein PAP7, which binds and brings to mitochondria the regulatory subunit RI␣ of the cAMP-dependent protein kinase (PKARI␣); and the hormone-induced PKA substrate, steroidogenic acute regulatory protein (StAR). Hormone treatment of MA-10 Leydig cells induced the co-localization of TSPO, PAP7, PKARI␣, and StAR in mitochondria, visualized by confocal microscopy, and the formation in living cells of a high molecular weight multimeric complex identified using photoactivable amino acids. The hormone-induced recruitment of exogenous TSPO in this complex was found to parallel the increased presence of 7-azi-5␣-cholestan-3␤-ol in the samples. Co-expression of Tspo, Pap7, PkarI␣, and Star genes resulted in the stimulation of steroid formation in both steroidogenic MA-10 and non-steroidogenic COS-F2-130 cells that were engineered to metabolize cholesterol. Disruption of these protein-protein interactions and specifically the PKARI␣-PAP7 and PAP7-TSPO interactions, using PAP7 mutants where the N0 area homologous to dual A-kinase-anchoring protein-1 or the acyl-CoA signature motif were deleted or using the peptide Ht31 known to disrupt the anchoring of PKA, inhibited both basal and hormone-induced steroidogenesis. These results suggest that the initiation of cAMP-induced protein-protein interactions results in the formation of a multivalent scaffold in the outer mitochondrial membrane that mediates the effect of hormones on mitochondrial cholesterol transport and steroidogenesis.Steroids are formed by several successive enzymatic transformations of the substrate cholesterol in the mitochondria and endoplasmic reticulum (1). The rate-determining step for steroidogenesis is the transport of the precursor, cholesterol, from intracellular sources into the mitochondria (2, 3). This step is regulated by trophic hormones, such as adrenocorticotropic hormone, in adrenocortical cells and luteinizing hormone in testicular Leydig and ovarian cells that act via G-protein-coupled receptors to activate adenylate cyclase and induce the formation of cAMP (1-3). Four molecules of cAMP bind to the regulatory (R) 2 subunits of the cAMP-dependent protein kinase (PKA) holoenzyme to release the catalytic subunits that phosphorylate specific substrates/effectors, thus transducing and amplifying the signal transmitted by the hormone (2-4). Protein phosphorylation has been shown to be one of the regulatory steps in hormone-stimulated steroid formation (2, 5). This is a highly efficient and rapid process where minimal amounts of cAMP are needed to induce a maximal rate of cholesterol transport and steroid synthesis within minutes upon expo...

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Section: Discussionmentioning

confidence: 99%

Protein-Protein Interactions Mediate Mitochondrial Cholesterol Transport and Steroid Biosynthesis

Rone

Papadopoulos

2006

Journal of Biological Chemistry

217

179

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“…It has been hypothesized that the close association of TSPO with VDAC (Gavish et al, 1999;McEnery et al, 1992) may help to ensure that the ROS generated via TSPO can actually affect VDAC. The reported grouping of TSPO molecules around VDAC, potentially reflecting TSPO polymerization (Golani et al, 2001;Veenman et al, 2002Veenman et al, , 2007, may help enhance the concentration of ROS generated by TSPO in the proximity of the VDAC, leading to apoptosis induction (see Section 9.3).…”

Section: Vdac and The Translocator Proteinmentioning

confidence: 99%

VDAC, a multi-functional mitochondrial protein regulating cell life and death

Shoshan‐Barmatz

Pinto

Zweckstetter

et al. 2010

Molecular Aspects of Medicine

644

731

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“…TSPO is mainly found on the OMM [340,345], where it is closely associated with VDAC [346]. It has been hypothesized that the close association of TSPO with VDAC allows ROS generated via TSPO to affect VDAC [296,347]. 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].…”

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

209

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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Hormonal Regulation of Peripheral Benzodiazepine Receptor Binding Properties Is Mediated by Subunit Interaction

Cited by 45 publications

References 52 publications

Protein-Protein Interactions Mediate Mitochondrial Cholesterol Transport and Steroid Biosynthesis

Protein-Protein Interactions Mediate Mitochondrial Cholesterol Transport and Steroid Biosynthesis

VDAC, a multi-functional mitochondrial protein regulating cell life and death

The mitochondrial voltage-dependent anion channel 1 in tumor cells

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