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1.
Hurtaud C Gelly C Chen Z Lévi-Meyrueis C Bouillaud F 《Cellular and molecular life sciences : CMLS》2007,64(14):1853-1860
Uncoupling protein 2 (UCP2) belongs to a family of transporters/exchangers of the mitochondrial inner membrane. Using cell
lines representing natural sites of UCP2 expression (macrophages, colonocytes, pancreatic beta cells), we show that UCP2 expression
is stimulated by glutamine at physiological concentrations. This control is exerted at the translational level. We demonstrate
that the upstream open reading frame (ORF1) in the 5’ untranslated region (5’UTR) of the UCP2 mRNA is required for this stimulation
to take place. Cloning of the 5’ UTR of the UCP2 mRNA in front of a GFP cDNA resulted in a reporter gene with which GFP expression
could be induced by glutamine. An effect of glutamine on translation of a given mRNA has not been identified before, and this
is the first evidence for a link between UCP2 and glutamine, an amino acid oxidized by immune cells or intestinal epithelium
and playing a role in the control of insulin secretion.
Received 26 January 2007; received after revision 16 April 2007; accepted 8 May 2007
C. Hurtaud, C. Gelly: These authors contributed equally to this work. 相似文献
2.
Opposite actions of testosterone and progesterone on UCP1 mRNA expression in cultured brown adipocytes 总被引:3,自引:0,他引:3
Rodriguez AM Monjo M Roca P Palou A 《Cellular and molecular life sciences : CMLS》2002,59(10):1714-1723
The brown adipose tissue (BAT) thermogenic response to diet-induced obesity and cold has been found to be gender dependent.
In the present work, we aimed to investigate the effects of the main physiological male and female sex hormones, i.e. testosterone,
progesterone and 17-β-estradiol, on the expression of uncoupling protein 1 (UCP1) – the main mediator of BAT thermogenesis
– and on UCP2 and lipid accumulation in rodent brown adipocytes differentiated in culture. Testosterone-treated cells showed
fewer and smaller lipid droplets than control cells and a dose-dependent inhibition of UCP1 mRNA expression, under adrenergic
stimulation by norepinephrine (NE). These effects were reverted by the androgen receptor antagonist flutamide, suggesting
they are dependent, at least in part, on the androgen receptor. Progesterone- and 17-β-estradiol-treated cells showed more
and larger lipid droplets and progesterone stimulated NE-induced UCP1 mRNA expression at the lower concentration tested, but
not at higher concentrations, suggesting that for brown adipocytes, this hormone is dose dependent. 17-β-Estradiol did not
have any remarkable effect either on UCP1 or UCP2 mRNA expression. Interestingly, the specific progesterone receptor antagonist
RU486 induced UCP1 and UCP2 mRNAs, including UCP1 mRNA expression in non-NE-treated brown adipocytes, suggesting a profound
effect of this anti-progestagen on brown adipocyte thermogenic capacity. Thus, are conclude that testosterone, 17-β-estradiol,
progesterone and RU486 have distinct actions on brown adipocytes, thus modulating UCP1 and UCP2 mRNA expression and/or lipid
accumulation, and that sex hormones are factors that may explain in part the gender-dependent BAT thermogenic response.
Received 24 June 2002; received after revision 20 August 2002; accepted 26 August 2002
RID="*"
ID="*"Corresponding author. 相似文献
3.
Hurtaud C Gelly C Bouillaud F Lévi-Meyrueis C 《Cellular and molecular life sciences : CMLS》2006,63(15):1780-1789
Uncoupling protein 2 (UCP2) belongs to a family of transporters of the mitochondrial inner membrane. In vivo low expression of UCP2 contrasts with a high UCP2 mRNA level, and induction of UCP2 expression occurs without change in mRNA
level, demonstrating a translational control. The UCP2 mRNA is characterized by a long 5′ untranslated region (5′UTR), in
which an upstream open reading frame (uORF) codes for a 36-amino-acid sequence. The 5′UTR and uORF have an inhibitory role
in the translation of UCP2. The present study demonstrates that the 3′ region of the uORF is a major determinant for this
inhibitory role. In this 3′ region, a single-base substitution that kept the codon sense unchanged significantly modified
UCP2 translation, whereas some important amino acid changes had no effect. We discuss our results within the framework of
the existing models explaining initiation of translation downstream of a uORF.
Received 22 March 2006; received after revision 19 May 2006; accepted 8 June 2006
C. Hurtaud and C. Gelly contributed equally to this work. 相似文献
4.
Prerna Malaney Vladimir N. Uversky Vrushank Davé 《Cellular and molecular life sciences : CMLS》2017,74(15):2783-2794
Proteoforms are specific molecular forms of protein products arising from a single gene that possess different structures and different functions. Therefore, a single gene can produce a large repertoire of proteoforms by means of allelic variations (mutations, indels, SNPs), alternative splicing and other pre-translational mechanisms, post-translational modifications (PTMs), conformational dynamics, and functioning. Resulting proteoforms that have different sizes, alternative splicing patterns, sets of post-translational modifications, protein–protein interactions, and protein–ligand interactions, might dramatically increase the functionality of the encoded protein. Herein, we have interrogated the tumor suppressor PTEN for its proteoforms and find that this protein exists in multiple forms with distinct functions and sub-cellular localizations. Furthermore, the levels of each PTEN proteoform in a given cell may affect its biological function. Indeed, the paradigm of the continuum model of tumor suppression by PTEN can be better explained by the presence of a continuum of PTEN proteoforms, diversity, and levels of which are associated with pathological outcomes than simply by the different roles of mutations in the PTEN gene. Consequently, understanding the mechanisms underlying the dysregulation of PTEN proteoforms by several genomic and non-genomic mechanisms in cancer and other diseases is imperative. We have identified different PTEN proteoforms, which control various aspects of cellular function and grouped them into three categories of intrinsic, function-induced, and inducible proteoforms. A special emphasis is given to the inducible PTEN proteoforms that are produced due to alternative translational initiation. The novel finding that PTEN forms dimers with biological implications supports the notion that PTEN proteoform–proteoform interactions may play hitherto unknown roles in cellular homeostasis and in pathogenic settings, including cancer. These PTEN proteoforms with unique properties and functionalities offer potential novel therapeutic opportunities in the treatment of various cancers and other diseases. 相似文献
5.
Morgado M Cairrão E Santos-Silva AJ Verde I 《Cellular and molecular life sciences : CMLS》2012,69(2):247-266
Vascular smooth muscle tone is controlled by a balance between the cellular signaling pathways that mediate the generation
of force (vasoconstriction) and release of force (vasodilation). The initiation of force is associated with increases in intracellular
calcium concentrations, activation of myosin light-chain kinase, increases in the phosphorylation of the regulatory myosin
light chains, and actin-myosin crossbridge cycling. There are, however, several signaling pathways modulating Ca2+ mobilization and Ca2+ sensitivity of the contractile machinery that secondarily regulate the contractile response of vascular smooth muscle to
receptor agonists. Among these regulatory mechanisms involved in the physiological regulation of vascular tone are the cyclic
nucleotides (cAMP and cGMP), which are considered the main messengers that mediate vasodilation under physiological conditions.
At least four distinct mechanisms are currently thought to be involved in the vasodilator effect of cyclic nucleotides and
their dependent protein kinases: (1) the decrease in cytosolic calcium concentration ([Ca2+]c), (2) the hyperpolarization of the smooth muscle cell membrane potential, (3) the reduction in the sensitivity of the contractile
machinery by decreasing the [Ca2+]c sensitivity of myosin light-chain phosphorylation, and (4) the reduction in the sensitivity of the contractile machinery
by uncoupling contraction from myosin light-chain phosphorylation. This review focuses on each of these mechanisms involved
in cyclic nucleotide-dependent relaxation of vascular smooth muscle under physiological conditions. 相似文献
6.
Cláudia Guimas Almeida Farzaneh Sadat Mirfakhar Catarina Perdigão Tatiana Burrinha 《Cellular and molecular life sciences : CMLS》2018,75(14):2577-2589
The increased production of the 42 aminoacids long beta-amyloid (Aβ42) peptide has been established as a causal mechanism of the familial early onset Alzheimer’s disease (AD). In contrast, the causal mechanisms of the late-onset AD (LOAD), that affects most AD patients, remain to be established. Indeed, Aβ42 accumulation has been detected more than 30 years before diagnosis. Thus, the mechanisms that control Aβ accumulation in LOAD likely go awry long before pathogenesis becomes detectable. Early on, APOE4 was identified as the biggest genetic risk factor for LOAD. However, since APOE4 is not present in all LOAD patients, genome-wide association studies of thousands of LOAD patients were undertaken to identify other genetic variants that could explain the development of LOAD. PICALM, BIN1, CD2AP, SORL1, and PLD3 are now with APOE4 among the identified genes at highest risk in LOAD that have been implicated in Aβ42 production. Recent evidence indicates that the regulation of the endocytic trafficking of the amyloid precursor protein (APP) and/or its secretases to and from sorting endosomes is determinant for Aβ42 production. Thus, here, we will review the described mechanisms, whereby these genetic risk factors can contribute to the enhanced endocytic production of Aβ42. Dissecting causal LOAD mechanisms of Aβ42 accumulation, underlying the contribution of each genetic risk factor, will be required to identify therapeutic targets for novel personalized preventive strategies. 相似文献
7.
Sheng-Ming Wu Wan-Li Cheng Crystal D. Lin Kwang-Huei Lin 《Cellular and molecular life sciences : CMLS》2013,70(11):1915-1936
The thyroid hormone 3,3′,5-triiodo-l-thyronine (T3) mediates several physiological processes, including embryonic development, cellular differentiation, metabolism, and the regulation of cell proliferation. Thyroid hormone receptors (TRs) generally act as heterodimers with the retinoid X receptor (RXR) to regulate target genes. In addition to their developmental and metabolic functions, TRs have been shown to play a tumor suppressor role, suggesting that their aberrant expression can lead to tumor transformation. Conversely, recent reports have shown an association between overexpression of wild-type TRs and tumor metastasis. Signaling crosstalk between T3/TR and other pathways or specific TR coregulators appear to affect tumor development. Since TR actions are complex as well as cell context-, tissue- and time-specific, aberrant expression of the various TR isoforms has different effects during diverse tumorigenesis. Therefore, elucidation of the T3/TR signaling mechanisms in cancers should facilitate the identification of novel therapeutic targets. This review provides a summary of recent studies focusing on the role of TRs in hepatocellular carcinomas (HCCs). 相似文献
8.
Liora Lindenboim Elisa Ferrando-May Christoph Borner Reuven Stein 《Cellular and molecular life sciences : CMLS》2013,70(16):3013-3027
Bax and Bak (Bax/Bak) are essential pro-apoptotic proteins of the Bcl-2 family that trigger mitochondrial outer membrane permeabilization (MOMP) in a Bcl-2/Bcl-xL-inhibitable manner. We recently discovered a new stress-related function for Bax/Bak—regulation of nuclear protein redistribution (NPR) from the nucleus to cytoplasm. This effect was independent of Bax/Bak N-terminus exposure and not inhibited by Bcl-xL over-expression. Here, we studied the molecular mechanism governing this novel non-canonical response. Wild-type (WT) and mutant versions of Bax were re-expressed in Bax/Bak double-knockout mouse embryonic fibroblasts and their ability to promote NPR, apoptotic events, and changes in lamin A mobility was examined. Our results show that, in this system, Bax expression was sufficient to restore NPR such as in WT cells undergoing apoptosis. This activity of Bax was uncoupled from cytochrome c release from the mitochondria (indicative of MOMP) and required its membrane localization, α helices 5/6, and the Bcl-2 homology 3 (BH3) domain. Moreover, enrichment of Bax in the nuclear envelope by the so-called Klarsicht/ANC-1/Syne-1 homology domain effectively triggered NPR as in WT Bax, but without inducing MOMP or cell death. Bax-induced NPR was associated with impairment in lamin A mobility, implying a connection between these two nuclear envelope-associated events. Overall, the results indicate a new MOMP-independent, stress-induced Bax function on the nuclear envelope. 相似文献
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The inhibitor of growth (ING) family of tumor suppressors has five members and is implicated in the control of apoptosis,
senescence, DNA repair, and cancer progression. However, little is known about ING activity in the regulation of cancer progression.
ING members and splice variants seem to behave differently with respect to cancer invasion and metastasis. Interaction with
histone trimethylated at lysine 4 (H3K4me3), hypoxia inducible factor-1 (HIF-1), p53, and nuclear factor kappa-B (NF-κB) are
potential mechanisms by which ING members exert effects on invasion and metastasis. Subcellular mislocalization, rapid protein
degradation, and to a lesser extent ING gene mutation are among the mechanisms responsible for inappropriate ING levels in cancer cells. The aim of this review is
to summarize the different roles of ING family tumor suppressors in cancer progression and the molecular mechanisms involved. 相似文献
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Delhommeau F Pisani DF James C Casadevall N Constantinescu S Vainchenker W 《Cellular and molecular life sciences : CMLS》2006,63(24):2939-2953
Myeloproliferative disorders (MPDs) are clonal haematopoietic malignancies involving the abnormal proliferation of myeloid
lineages. The World Health Organisation (WHO) classification of haematopoietic malignancies distinguishes MPDs from myelodysplastic/
myeloproliferative disorders and systemic mastocytosis. These malignancies frequently involve constitutive tyrosine kinase
activity, resulting from either oncogenic fusion protein production or from point mutations. Chronic myelogenous leukaemia
is the model used for studies of the consequences of such molecular defects. However, the heterogeneity of the clinical course
of MPDs should be seen in a more rationale conceptual framework, including the many molecular events associated with these
diseases. This review focuses on the various tyrosine kinase-related molecular mechanisms underlying both MPDs and rare diseases
with myeloproliferative features. We pay particular attention to the newly identified JAK2 V617F mutation in polycythaemia
vera, essential thrombocythaemia and idiopathic myelofibrosis and deal with disease heterogeneity and putative additional
molecular mechanisms.
Received 9 June 2006; received after revision 28 July 2006; accepted 11 September 2006 相似文献
14.
Molecular basis of autosomal-dominant polycystic kidney disease 总被引:5,自引:0,他引:5
Gallagher AR Hidaka S Gretz N Witzgall R 《Cellular and molecular life sciences : CMLS》2002,59(4):682-693
Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic diseases in humans. The discovery
that mutations in the PKD1 and PKD2 genes are responsible for ADPKD has sparked extensive research efforts into the physiological and pathogenetic role of polycystin-1
and polycystin-2, the proteins encoded by these two genes. While polycystin-1 may mediate the contact among cells or between
cells and the extracellular matrix, a lot of evidence suggests that polycystin-2 represents an endoplasmic reticulum-bound
cation channel. Cyst development has been compared to the growth of benign tumors and this view is highlighted by the model
that a somatic mutation in addition to the germline mutation is responsible for cystogenesis (two-hit model of cyst formation).
Since in vitro polycystin-1 and polycystin-2 interact through their COOH termini, the two proteins possibly act in a common
pathway, which controls the width of renal tubules. The loss of one protein may lead to a disruption of this pathway and to
the uncontrolled expansion of tubules. Our increasing knowledge of the molecular events in ADPKD has also started to be useful
in designing novel diagnostic and therapeutic strategies.
Received 12 September 2001; received after revision 7 November 2001; accepted 7 November 2001 相似文献
15.
Marthe-Susanna Wegner Nina Schömel Lisa Gruber Stephanie Beatrice Örtel Matti Aleksi Kjellberg Peter Mattjus Jennifer Kurz Sandra Trautmann Bing Peng Martin Wegner Manuel Kaulich Robert Ahrends Gerd Geisslinger Sabine Grösch 《Cellular and molecular life sciences : CMLS》2018,75(18):3393-3410
The UDP-glucose ceramide glucosyltransferase (UGCG) is a key enzyme in the synthesis of glycosylated sphingolipids, since this enzyme generates the precursor for all complex glycosphingolipids (GSL), the GlcCer. The UGCG has been associated with several cancer-related processes such as maintaining cancer stem cell properties or multidrug resistance induction. The precise mechanisms underlying these processes are unknown. Here, we investigated the molecular mechanisms occurring after UGCG overexpression in breast cancer cells. We observed alterations of several cellular properties such as morphological changes, which enhanced proliferation and doxorubicin resistance in UGCG overexpressing MCF-7 cells. These cellular effects seem to be mediated by an altered composition of glycosphingolipid-enriched microdomains (GEMs), especially an accumulation of globotriaosylceramide (Gb3) and glucosylceramide (GlcCer), which leads to an activation of Akt and ERK1/2. The induction of the Akt and ERK1/2 signaling pathway results in an increased gene expression of multidrug resistance protein 1 (MDR1) and anti-apoptotic genes and a decrease of pro-apoptotic gene expression. Inhibition of the protein kinase C (PKC) and phosphoinositide 3 kinase (PI3K) reduced MDR1 gene expression. This study discloses how changes in UGCG expression impact several cellular signaling pathways in breast cancer cells resulting in enhanced proliferation and multidrug resistance. 相似文献
16.
Redox modulation of the NMDA receptor 总被引:9,自引:0,他引:9
Redox modulation has been recognized to be an important mechanism of regulation for the N-methyl-D-aspartate (NMDA) receptor. Sulfhydryl reducing agents enhance, whereas oxidizing agents decrease, NMDA-evoked currents. Multiple cysteine residues located in different NMDA receptor subunits have been identified as molecular determinants underlying redox modulation. The NMDA receptor is also regulated by nitric oxide (NO)-related species directly, not involving cyclic GMP, but the molecular mechanism of this action has heretofore not been entirely clear. The confusion arose at least partly due to the fact that various redox forms of NO (NO+, NO*, NO-, each having an additional electron compared with the previous) have distinct mechanisms of action. Recently, a critical cysteine residue (Cys 399) on the NR2A subunit has been shown to react under physiological conditions with NO by S-nitrosylation (transfer of the NO+ to cysteine thiol) or by reaction with NO- (nitroxyl anion) to underlie this form of modulation. 相似文献
17.
Julia Scharnert Lilo Greune Dagmar Zeuschner Marie-Luise Lubos M. Alexander Schmidt Christian Rüter 《Cellular and molecular life sciences : CMLS》2013,70(24):4809-4823
Extracellular Gram-negative pathogenic bacteria target essential cytoplasmic processes of eukaryotic cells by using effector protein delivery systems such as the type III secretion system (T3SS). These secretion systems directly inject effector proteins into the host cell cytoplasm. Among the T3SS-dependent Yop proteins of pathogenic Yersinia, the function of the effector protein YopM remains enigmatic. In a recent study, we demonstrated that recombinant YopM from Yersinia enterocolitica enters host cells autonomously without the presence of bacteria and thus identified YopM as a novel bacterial cell-penetrating protein. Following entry YopM down-regulates expression of pro-inflammatory cytokines such as tumor necrosis factor α. These properties earmark YopM for further development as a novel anti-inflammatory therapeutic. To elucidate the uptake and intracellular targeting mechanisms of this bacterial cell-penetrating protein, we analyzed possible routes of internalization employing ultra-cryo electron microscopy. Our results reveal that under physiological conditions, YopM enters cells predominantly by exploiting endocytic pathways. Interestingly, YopM was detected free in the cytosol and inside the nucleus. We could not observe any colocalization of YopM with secretory membranes, which excludes retrograde transport as the mechanism for cytosolic release. However, our findings indicate that direct membrane penetration and/or an endosomal escape of YopM contribute to the cytosolic and nuclear localization of the protein. Surprisingly, even when endocytosis is blocked, YopM was found to be associated with endosomes. This suggests an intracellular endosome-associated transport of YopM. 相似文献
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Anne Nehlig Angie Molina Sylvie Rodrigues-Ferreira Stéphane Honoré Clara Nahmias 《Cellular and molecular life sciences : CMLS》2017,74(13):2381-2393
The regulation of microtubule dynamics is critical to ensure essential cell functions, such as proper segregation of chromosomes during mitosis or cell polarity and migration. End-binding protein 1 (EB1) is a plus-end-tracking protein (+TIP) that accumulates at growing microtubule ends and plays a pivotal role in the regulation of microtubule dynamics. EB1 autonomously binds an extended tubulin-GTP/GDP-Pi structure at growing microtubule ends and acts as a molecular scaffold that recruits a large number of regulatory +TIPs through interaction with CAP-Gly or SxIP motifs. While extensive studies have focused on the structure of EB1-interacting site at microtubule ends and its role as a molecular platform, the mechanisms involved in the negative regulation of EB1 have only started to emerge and remain poorly understood. In this review, we summarize recent studies showing that EB1 association with MT ends is regulated by post-translational modifications and affected by microtubule-targeting agents. We also present recent findings that structural MAPs, that have no tip-tracking activity, physically interact with EB1 to prevent its accumulation at microtubule plus ends. These observations point out a novel concept of “endogenous EB1 antagonists” and emphasize the importance of finely regulating EB1 function at growing microtubule ends. 相似文献
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