scholarly journals Translocator protein and steroidogenesis

2018 ◽  
Vol 475 (5) ◽  
pp. 901-904 ◽  
Author(s):  
Barbara Costa ◽  
Eleonora Da Pozzo ◽  
Claudia Martini
Keyword(s):  
Genetic Manipulation ◽  
Translocator Protein ◽  
Accurate Information ◽  
Hormonal Stimulation ◽  
Steroid Synthesis ◽  
Genetic Manipulations ◽  
Biochemical Journal ◽  
Human Polymorphism

Two interesting papers by Barren et al. and Owen et al. have been very recently published in Biochemical Journal, reporting the role of translocator protein (TSPO) in steroidogenesis. The involvement of TSPO in the steroid biosynthesis has been suggested by 30 years of researches, using biochemical, pharmacological and genetic experimental approaches. In the last 3 years, however, the TSPO involvement in steroidogenesis has been intensively and profoundly discussed. Using in vivo genetic manipulations aimed at deleting TSPO, some researchers have excluded its role in steroid production. Other research groups, using similar genetic manipulation techniques, have presented different results, corroborating the role of TSPO in steroidogenesis, in particular, when hormonal stimulation occurs. In this scenario, the publications by Barron et al. about ‘Steroidogenic abnormalities in translocator protein knockout mice and significance in the aging male’ and by Owen et al. about ‘TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis’ are part of this debate and provide further and more accurate information supporting the importance of TSPO as a steroidogenesis regulator.

scholarly journals TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

2016 ◽  
Vol 473 (2) ◽  
pp. 107-121 ◽  
Author(s):  
Jemma Gatliff ◽  
Michelangelo Campanella
Keyword(s):  
Neurological Diseases ◽  
Anion Channel ◽  
Translocator Protein ◽  
Endocrine Regulation ◽  
Voltage Dependent Anion Channel ◽  
Steroid Synthesis ◽  
Cellular Processes ◽  
Cellular Events ◽  
Voltage Dependent

The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

scholarly journals L1CAM promotes ovarian cancer stemness and tumor initiation via FGFR1/SRC/STAT3 signaling

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Marco Giordano ◽  
Alessandra Decio ◽  
Chiara Battistini ◽  
Micol Baronio ◽  
Fabrizio Bianchi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Genetic Manipulation ◽  
Tumor Formation ◽  
In Vitro Assays ◽  
Tumor Initiation ◽  
Loss Of Function ◽  
Stat3 Signaling

Abstract Background Cancer stem cells (CSC) have been implicated in tumor progression. In ovarian carcinoma (OC), CSC drive tumor formation, dissemination and recurrence, as well as drug resistance, thus contributing to the high death-to-incidence ratio of this disease. However, the molecular basis of such a pathogenic role of ovarian CSC (OCSC) has been elucidated only to a limited extent. In this context, the functional contribution of the L1 cell adhesion molecule (L1CAM) to OC stemness remains elusive. Methods The expression of L1CAM was investigated in patient-derived OCSC. The genetic manipulation of L1CAM in OC cells provided gain and loss-of-function models that were then employed in cell biological assays as well as in vivo tumorigenesis experiments to assess the role of L1CAM in OC cell stemness and in OCSC-driven tumor initiation. We applied antibody-mediated neutralization to investigate L1CAM druggability. Biochemical approaches were then combined with functional in vitro assays to study the molecular mechanisms underlying the functional role of L1CAM in OCSC. Results We report that L1CAM is upregulated in patient-derived OCSC. Functional studies showed that L1CAM promotes several stemness-related properties in OC cells, including sphere formation, tumor initiation and chemoresistance. These activities were repressed by an L1CAM-neutralizing antibody, pointing to L1CAM as a druggable target. Mechanistically, L1CAM interacted with and activated fibroblast growth factor receptor-1 (FGFR1), which in turn induced the SRC-mediated activation of STAT3. The inhibition of STAT3 prevented L1CAM-dependent OC stemness and tumor initiation. Conclusions Our study implicate L1CAM in the tumorigenic function of OCSC and point to the L1CAM/FGFR1/SRC/STAT3 signaling pathway as a novel driver of OC stemness. We also provide evidence that targeting this pathway can contribute to OC eradication.

scholarly journals TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis

2017 ◽  
Vol 474 (23) ◽  
pp. 3985-3999 ◽  
Author(s):  
David R. Owen ◽  
Jinjiang Fan ◽  
Enrico Campioli ◽  
Sathvika Venugopal ◽  
Andrew Midzak ◽  
...  
Keyword(s):  
Translocator Protein ◽  
Rat Tissues ◽  
Steroid Synthesis ◽  
Rate Limiting Step ◽  
Steroid Dependent ◽  
Proliferation And Apoptosis ◽  
Numerous Cell ◽  
Human Polymorphism ◽  
Hormone Biosynthesis ◽  
Rate Limiting

The 18 kDa translocator protein (TSPO) is a ubiquitous conserved outer mitochondrial membrane protein implicated in numerous cell and tissue functions, including steroid hormone biosynthesis, respiration, cell proliferation, and apoptosis. TSPO binds with high affinity to cholesterol and numerous compounds, is expressed at high levels in steroid-synthesizing tissues, and mediates cholesterol import into mitochondria, which is the rate-limiting step in steroid formation. In humans, the rs6971 polymorphism on the TSPO gene leads to an amino acid substitution in the fifth transmembrane loop of the protein, which is where the cholesterol-binding domain of TSPO is located, and this polymorphism has been associated with anxiety-related disorders. However, recent knockout mouse models have provided inconsistent conclusions of whether TSPO is directly involved in steroid synthesis. In this report, we show that TSPO deletion mutations in rat and its corresponding rs6971 polymorphism in humans alter adrenocorticotropic hormone-induced plasma corticosteroid concentrations. Rat tissues examined show increased cholesteryl ester accumulation, and neurosteroid formation was undetectable in homozygous rats. These results also support a role for TSPO ligands in diseases with steroid-dependent stress and anxiety elements.

Regulation of the AMPK-related protein kinases by ubiquitination

2008 ◽  
Vol 411 (2) ◽  
pp. e9-e10 ◽  
Author(s):  
David M. Thomson ◽  
Marc D. H. Hansen ◽  
William W. Winder
Keyword(s):  
Deubiquitinating Enzyme ◽  
Polyubiquitin Chains ◽  
Kinase Substrate ◽  
Biochemical Journal ◽  
Substrate Level ◽  
Amp Activated Protein Kinase ◽  
And Control

How can a constitutively active ‘master’ kinase with numerous downstream targets preferentially phosphorylate one or more of these without influencing all simultaneously? How might such a system be switched off? The characterization of the role of deubiquitination in regulating the phosphorylation and activation of AMPK (AMP-activated protein kinase)-related kinases by LKB1 suggests a novel and interesting mechanism for conferring signal transduction specificity and control at the kinase substrate level. In this issue of the Biochemical Journal, Al-Hakim et al. show that the AMPK-related kinases NUAK1 (AMPK-related kinase 5) and MARK4 (microtubule-affinity-regulating kinase 4) are polyubiquitinated in vivo and that they serve as substrates of the deubiquitinating enzyme USP9X; furthermore, the first evidence is provided for regulation of AMPK-related kinase family members mediated via unusual Lys29/Lys33 polyubiquitin chains, rather than the more common Lys48/Lys63 linkages.

In Vivo Recordings of Bulbospinal Excitation in Adult Mouse Forelimb Motoneurons

2004 ◽  
Vol 92 (3) ◽  
pp. 1958-1962 ◽  
Author(s):  
Bror Alstermark ◽  
Jun Ogawa
Keyword(s):  
Motor Control ◽  
Adult Mouse ◽  
Corticospinal Tract ◽  
Genetic Manipulation ◽  
Medial Longitudinal Fasciculus ◽  
Intracellular Recordings ◽  
Descending Systems ◽  
Monosynaptic Excitation

Here we report on pyramidal and reticulospinal excitation in forelimb motoneurons in the adult mouse using intracellular recordings in vivo. The results have been obtained in BALB/C mice, which were anesthetized with midazolam fentanyl/fluanison. In contrast to the rat, only weak and infrequent pyramidal excitation could be evoked with a minimal trisynaptic linkage. Disynaptic reticulospinal excitation could always be evoked, as well as monosynaptic excitation from the medial longitudinal fasciculus. The results suggest that the reticulospinal pathway in the mouse is important in voluntary motor control of the forelimbs and that the role of the corticospinal tract might be different in mouse compared with rat. Our study provides an opening for studying the effect of genetic manipulation on specified descending systems in the mouse in vivo.

Mitochondrial matrix calcium ions regulate energy production in myocardium: A cytochemical study

1990 ◽  
Vol 48 (2) ◽  
pp. 166-167
Author(s):  
W.A. Jacob ◽  
R. Hertsens ◽  
A. Van Bogaert ◽  
M. De Smet
Keyword(s):  
Energy Metabolism ◽  
Calcium Ions ◽  
Energy Production ◽  
Regulation Of Respiration ◽  
Free Calcium ◽  
Mitochondrial Matrix ◽  
Cytochemical Study ◽  
Nmr Techniques

In the past most studies of the control of energy metabolism focus on the role of the phosphorylation potential ATP/ADP.Pi on the regulation of respiration. Studies using NMR techniques have demonstrated that the concentrations of these compounds for oxidation phosphorylation do not change appreciably throughout the cardiac cycle and during increases in cardiac work. Hence regulation of energy production by calcium ions, present in the mitochondrial matrix, has been the object of a number of recent studies.Three exclusively intramitochondnal dehydrogenases are key enzymes for the regulation of oxidative metabolism. They are activated by calcium ions in the low micromolar range. Since, however, earlier estimates of the intramitochondnal calcium, based on equilibrium thermodynamic considerations, were in the millimolar range, a physiological correlation was not evident. The introduction of calcium-sensitive probes fura-2 and indo-1 made monitoring of free calcium during changing energy metabolism possible. These studies were performed on isolated mitochondria and extrapolation to the in vivo situation is more or less speculative.

Meiotic CENP-C is a shepherd: bridging the space between the centromere and the kinetochore in time and space

2020 ◽  
Vol 64 (2) ◽  
pp. 251-261
Author(s):  
Jessica E. Fellmeth ◽  
Kim S. McKim
Keyword(s):  
Chromosome Segregation ◽  
New Technologies ◽  
Early Prophase ◽  
Unique Role ◽  
Kinetochore Assembly ◽  
M Phase ◽  
In Vivo Analysis ◽  
Meiosis I

Abstract While many of the proteins involved in the mitotic centromere and kinetochore are conserved in meiosis, they often gain a novel function due to the unique needs of homolog segregation during meiosis I (MI). CENP-C is a critical component of the centromere for kinetochore assembly in mitosis. Recent work, however, has highlighted the unique features of meiotic CENP-C. Centromere establishment and stability require CENP-C loading at the centromere for CENP-A function. Pre-meiotic loading of proteins necessary for homolog recombination as well as cohesion also rely on CENP-C, as do the main scaffolding components of the kinetochore. Much of this work relies on new technologies that enable in vivo analysis of meiosis like never before. Here, we strive to highlight the unique role of this highly conserved centromere protein that loads on to centromeres prior to M-phase onset, but continues to perform critical functions through chromosome segregation. CENP-C is not merely a structural link between the centromere and the kinetochore, but also a functional one joining the processes of early prophase homolog synapsis to late metaphase kinetochore assembly and signaling.

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