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Références bibliographiques | 11 Disponible | Voir toutes les références
|Aperçu de la référence bibliographique||Nº PubMed|
|When cytokinin, a plant hormone, meets the adenosine A2A receptor: a novel neuroprotectant and lead for treating neurodegenerative disorders? |
Yi-Chao Lee,Ying-Chen Yang,Chuen-Lin Huang,Tsun-Yung Kuo,Jung-Hsin Lin,De-Ming Yang,Nai-Kuei Huang
PloS one 7 2012
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It is well known that cytokinins are a class of phytohormones that promote cell division in plant roots and shoots. However, their targets, biological functions, and implications in mammalian systems have rarely been examined. In this study, we show that one cytokinin, zeatin riboside, can prevent pheochromocytoma (PC12) cells from serum deprivation-induced apoptosis by acting on the adenosine A(2A) receptor (A(2A)-R), which was blocked by an A(2A)-R antagonist and a protein kinase A (PKA) inhibitor, demonstrating the functional ability of zeatin riboside by mediating through A(2A)-R signaling event. Since the A(2A)-R was implicated as a therapeutic target in treating Huntington's disease (HD), a cellular model of HD was applied by transfecting mutant huntingtin in PC12 cells. By using filter retardation assay and confocal microscopy we found that zeatin riboside reversed mutant huntingtin (Htt)-induced protein aggregations and proteasome deactivation through A(2A)-R signaling. PKA inhibitor blocked zeatin riboside-induced suppression of mutant Htt aggregations. In addition, PKA activated proteasome activity and reduced mutant Htt protein aggregations. However, a proteasome inhibitor blocked both zeatin riboside-and PKA activator-mediated suppression of mutant Htt aggregations, confirming mediation of the A(2A)-R/PKA/proteasome pathway. Taken together, zeatin riboside might have therapeutic potential as a novel neuroprotectant and a lead for treating neurodegenerative disorders.
|C terminus of Hsc70-interacting protein (CHIP)- mediated degradation of hippocampal estrogen receptor-alpha and the critical period hypothesis of estrogen neuroprotection. |
Zhang QG, Han D, Wang RM, Dong Y, Yang F, Vadlamudi RK, Brann DW
Proceedings of the National Academy of Sciences of the United States of America 108 E617-24. Epub 2011 Aug 1. 2011
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Recent work suggests that timing of 17β-estradiol (E2) therapy may be critical for observing a beneficial neural effect. Along these lines, E2 neuroprotection, but not its uterotropic effect, was shown to be lost following long-term E2 deprivation (LTED), and this effect was associated with a significant decrease of estrogen receptor-α (ERα) in the hippocampus but not the uterus. The purpose of the current study was to determine the mechanism underlying the ERα decrease and to determine whether aging leads to a similar loss of hippocampal ERα and E2 sensitivity. The results of the study show that ERα in the rat hippocampal CA1 region but not the uterus undergoes enhanced interaction with the E3 ubiquitin ligase C terminus of heat shock cognate protein 70 (Hsc70)-interacting protein (CHIP) that leads to its ubiquitination/proteasomal degradation following LTED (10-wk ovariectomy). E2 treatment initiated before but not after LTED prevented the enhanced ERα-CHIP interaction and ERα ubiquitination/degradation and was fully neuroprotective against global cerebral ischemia. Administration of a proteasomal inhibitor or CHIP antisense oligonucleotides to knock down CHIP reversed the LTED-induced down-regulation of ERα. Further work showed that these observations extended to natural aging, because aged rats showed enhanced CHIP interaction; ubiquitination and degradation of both hippocampal ERα and ERβ; and, importantly, a correlated loss of E2 neuroprotection against global cerebral ischemia. In contrast, E2 administration to middle-aged rats was still capable of exerting neuroprotection. As a whole, the study provides support for a \"critical period\" for E2 neuroprotection of the hippocampus and provides important insight into the mechanism underlying the critical period.Comment inProc Natl Acad Sci U S A. 2011 Aug 30;108(35):14375-6.
|Proteasome inhibition with bortezomib depletes plasma cells and autoantibodies in experimental autoimmune myasthenia gravis. |
Alejandro M Gomez,Kathleen Vrolix,Pilar Martínez-Martínez,Peter C Molenaar,Marko Phernambucq,Eline van der Esch,Hans Duimel,Fons Verheyen,Reinhard E Voll,Rudolf A Manz,Marc H De Baets,Mario Losen
Journal of immunology (Baltimore, Md. : 1950) 186 2011
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Bortezomib, an inhibitor of proteasomes, has been reported to reduce autoantibody titers and to improve clinical condition in mice suffering from lupus-like disease. Bortezomib depletes both short- and long-lived plasma cells; the latter normally survive the standard immunosuppressant treatments targeting T and B cells. These findings encouraged us to test whether bortezomib is effective for alleviating the symptoms in the experimental autoimmune myasthenia gravis (EAMG) model for myasthenia gravis, a disease that is characterized by autoantibodies against the acetylcholine receptor (AChR) of skeletal muscle. Lewis rats were immunized with saline (control, n = 36) or Torpedo AChR (EAMG, n = 54) in CFA in the first week of an experimental period of 8 wk. After immunization, rats received twice a week s.c. injections of bortezomib (0.2 mg/kg in saline) or saline injections. Bortezomib induced apoptosis in bone marrow cells and reduced the amount of plasma cells in the bone marrow by up to 81%. In the EAMG animals, bortezomib efficiently reduced the rise of anti-AChR autoantibody titers, prevented ultrastructural damage of the postsynaptic membrane, improved neuromuscular transmission, and decreased myasthenic symptoms. This study thus underscores the potential of the therapeutic use of proteasome inhibitors to target plasma cells in Ab-mediated autoimmune diseases.
|Inhibition of autophagy in the heart induces age-related cardiomyopathy. |
Manabu Taneike,Osamu Yamaguchi,Atsuko Nakai,Shungo Hikoso,Toshihiro Takeda,Isamu Mizote,Takafumi Oka,Takahito Tamai,Jota Oyabu,Tomokazu Murakawa,Kazuhiko Nishida,Takahiko Shimizu,Masatsugu Hori,Issei Komuro,Takuji Shirasawa Takuji Shirasawa,Noboru Mizushima,Kinya Otsu
Autophagy 6 2010
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Constitutive autophagy is important for control of the quality of proteins and organelles to maintain cell function. Damaged proteins and organelles accumulate in aged organs. We have previously reported that cardiac-specific Atg5 (autophagy-related gene 5)-deficient mice, in which the gene was floxed out early in embryogenesis, were born normally, and showed normal cardiac function and structure up to 10 weeks old. In the present study, to determine the longer-term consequences of Atg5-deficiency in the heart, we monitored cardiac-specific Atg5-deficient mice for further 12 months. First, we examined the age-associated changes of autophagy in the wild-type mouse heart. The level of autophagy, as indicated by decreased LC3-II (microtubule-associated protein 1 light chain 3-II) levels, in the hearts of 6-, 14- or 26-month-old mice was lower than that of 10-week-old mice. Next, we investigated the cardiac function and life-span in cardiac-specific Atg5-deficient mice. The Atg5-deficient mice began to die after the age of 6 months. Atg5-deficient mice exhibited a significant increase in left ventricular dimension and decrease in fractional shortening of the left ventricle at the age of 10 months, compared to control mice, while they showed similar chamber size and contractile function at the age of 3 months. Ultrastructural analysis revealed a disorganized sarcomere structure and collapsed mitochondria in 3- and 10-month-old Atg5-deficient mice, with decreased mitochondrial respiratory functions. These results suggest that continuous constitutive autophagy has a crucial role in maintaining cardiac structure and function.
|An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis. |
Z Li,Q Zhang,J-H Mao,A Weise,K Mrasek,X Fan,X Zhang,T Liehr,K H Lu,A Balmain,W-W Cai
Oncogene 29 2010
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There is a gap between the initial formation of cells carrying radiation-induced genetic damage and their contribution to cancer development. Herein, we reveal a previously uncharacterized gene FATS through a genome-wide approach and demonstrate its essential role in regulating the abundance of p21 in surveillance of genome integrity. A large exon coding the NH2-terminal domain of FATS, deleted in spontaneous mouse lymphomas, is much more frequently deleted in radiation-induced mouse lymphomas. Its human counterpart is a fragile site gene at a previously identified loss of heterozygosity site. FATS is essential for maintaining steady-state level of p21 protein and sustaining DNA damage checkpoint. Furthermore, the NH2-terminal FATS physically interacts with histone deacetylase 1 (HDAC1) to enhance the acetylation of endogenous p21, leading to the stabilization of p21. Our results reveal a molecular linkage between p21 abundance and radiation-induced carcinogenesis.
|Bcl-2 family proteins contribute to apoptotic resistance in lung cancer multicellular spheroids. |
Tsung-Ming Yang,Dario Barbone,Dean A Fennell,V Courtney Broaddus
American journal of respiratory cell and molecular biology 41 2009
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Combinatorial therapies using the proteasome inhibitor, bortezomib, have been found to induce synergistic apoptosis in cancer cells grown as monolayers; however, three-dimensional spheroid culture may be a better model for the multicellular resistance found in solid tumors, such as lung cancer. We tested the combinatorial apoptotic strategy of using bortezomib together with TNF-related apoptosis-inducing ligand (TRAIL), both in monolayers and in spheroids of A549 lung cancer cells. Indeed, bortezomib plus TRAIL induced synergistic apoptosis in A549 cells grown as monolayers, but had little effect on A549 cells grown as three-dimensional multicellular spheroids. The acquired resistance of spheroids was not due to a limitation of diffusion, to survival pathways, such as NF-kappaB or PI3K/Akt/mTOR, or to the up-regulation of FLIP(S) (Fas-associated death domain-like IL-1 beta-converting enzyme inhibitory protein, short). We then investigated a role for the Bcl-2 family of anti- and proapoptotic proteins. When cells formed spheroids, antiapoptotic Bcl-2 increased, whereas antiapoptotic Mcl-1 decreased. ABT-737, a small molecule that inhibits Bcl-2, but not Mcl-1, abolished the multicellular resistance of A549 spheroids to bortezomib plus TRAIL. In another lung cancer cell line, H1299, acquisition of multicellular resistance in spheroids was also accompanied by an increase in Bcl-2 and decrease in Mcl-1. In H1299 spheroids compared with those of A549, however, Mcl-1 remained higher, and Mcl-1 knockdown was more effective than ABT-737 in removing multicellular resistance. Our study suggests that the balance of Bcl-2 family proteins contributes to the acquired multicellular resistance of spheroids, and suggests a possible target for improving the response of lung cancer to bortezomib therapies.Article en texte intégral
|The proteasome inhibitor bortezomib aggravates renal ischemia-reperfusion injury. |
Huber, Julia M, et al.
Am. J. Physiol. Renal Physiol., 297: F451-60 (2009) 297 F451 2009
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Bortezomib is a well-established treatment option for patients with multiple myeloma (MM). It is a selective and reversible inhibitor of the proteasome that is responsible for the degradation of many regulatory proteins that are involved in apoptosis, cell-cycle regulation, or transcription. Because patients with MM are prone to develop acute renal failure, we evaluated the influence of bortezomib on renal ischemia-reperfusion injury (IRI). Mice were subjected to renal IRI by having the renal pedicles clamped for 30 min followed by reperfusion for 3, 24, and 48 h. Mice were either pretreated with 0.5 mg/kg body wt bortezomib or vehicle intravenously 12 h before induction of IRI. Serum creatinine and tubular necrosis were significantly increased in bortezomib compared with vehicle-treated mice. The inflammatory response was found to be significantly decreased in bortezomib-treated mice as reflected by a decreased infiltration of CD4(+) T cells and a significantly decreased Th1 cytokine expression in the kidneys. In contrast, apoptosis was significantly increased in kidneys of bortezomib-treated mice compared with vehicle-treated controls. Increased numbers of TUNEL-positive cells/mm(2) and increased mRNA expression of proapoptotic factors were detected in kidneys of bortezomib-treated mice. Of note, p21, a cell senescence marker, was also significantly increased in kidneys of bortezomib-treated mice. In summary, we provide evidence that bortezomib worsens the outcome of renal IRI by leading to increased apoptosis of tubular cells despite decreased infiltrating T cells and proinflammatory mediators.
|Modulating the hypoxia-inducible factor signaling pathway as a therapeutic modality to regulate retinal angiogenesis. |
M DeNiro,O Alsmadi,F Al-Mohanna
Experimental eye research 89 2009
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Hypoxia-inducible factor (HIF) signaling cascade plays a critical role in angiogenesis by activating the transcription of genes encoding angiogenic growth factors. This study evaluated the effects of YC-1, a HIF-1 inhibitor, on the morphological, biochemical and molecular changes in human retinal microvascular endothelial cells. We found that YC-1 suppressed vascular endothelial cell proliferation, migration and tube formation, while it significantly increased the proteasome activity. Moreover, YC-1 induced a G(0)/G(1) cell-cycle arrest, whereas it exerted only an insignificant proapoptotic effects. Under normoxia or hypoxia, YC-1 did not alter the morphology or the cell viability. Additionally, under hypoxic conditions, YC-1 downregulated HIF-2alpha, VEGF, EPO, ET-1, and MMP-9 mRNA and protein levels, this was accompanied by a significant decrease in the MMP-9 activity. YC-1 decreased the basal expression of HIF-1alpha protein under normoxia, whereas it inhibited HIF-1alpha protein synthesis, stability, and nuclear translocation mechanisms under hypoxia. Furthermore, in a 3D collagen matrix model using mouse retinal explants cultured under normoxic and hypoxic conditions, YC-1; (1) inhibited outgrowth of new vessel sprouts; (2) reduced VEGF expression; (3) dramatically decreased the vessels immunoreactivities for CD31 and von Willebrand Factor (vWF); and (4) was highly effective in reducing the vascular density within the retina, compared to controls. These findings indicate that YC-1 possesses several antiangiogenic properties, both in vitro and ex vivo, which could be exploited as valuable therapeutic potentials to inhibit formation and the growth of new retinal vessels in the hypoxic retina.
|Curcumin suppresses AP1 transcription factor-dependent differentiation and activates apoptosis in human epidermal keratinocytes. |
Sivaprakasam Balasubramanian, Richard L Eckert
The Journal of biological chemistry 282 6707-15 2007
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The diet-derived cancer preventive agent, curcumin, inhibits skin cancer cell proliferation and tumor formation. However, its effect on normal human keratinocyte differentiation, proliferation, and apoptosis has not been adequately studied. Involucrin (hINV) is a marker of keratinocyte differentiation and a useful model for the study of chemopreventive agent action. We show that curcumin suppresses the differentiation agent-dependent activation of hINV gene expression and that an AP1 transcription factor DNA binding site in the hINV gene is required for this regulation. A protein kinase C, Ras, MEKK1, MEK3 signaling cascade controls hINV expression by regulating AP1 factor level. Curcumin treatment inhibits the novel protein kinase C-, Ras-, and MEKK1-dependent activation of hINV promoter activity and reduces the differentiation agent-dependent increase in AP1 factor level and DNA binding. This reduction requires proteasome function. In addition, curcumin treatment reduces cell number, which is associated with a reduced cyclin and cdk1 levels. Curcumin treatment also suppresses the Bcl-xL level, leading to reduced mitochondrial membrane potential and increased cleavage of procaspases and poly(ADP-ribose) polymerase. These studies provide important insights regarding the mechanism whereby curcumin acts as a chemopreventive agent in normal human epidermis.
|Lithium leads to an increased FRQ protein stability and to a partial loss of temperature compensation in the Neurospora circadian clock. |
Jolma, Ingunn W, et al.
J. Biol. Rhythms, 21: 327-34 (2006) 2006
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In many organisms, the presence of lithium leads to an increase of the circadian period length. In Neurospora crassa, it was earlier found that lithium results in a decrease of overall growth and increased circadian periods. In this article, the authors show that lithium leads to a reduction of FRQ degradation with elevated FRQ levels and to a partial loss of temperature compensation. At a concentration of 13 mM lithium, FRQ degradation is reduced by about 60% while, surprisingly, the activity of the 20S proteasome remains unaffected. Experiments and model calculations have shown that the stability of FRQ is dependent on its phosphorylation state and that increased FRQ protein stabilities lead to increased circadian periods, consistent with the observed increase of the period when lithium is present. Because in Neurospora the proteasome activity is unaffected by lithium concentrations that lead to significant FRQ stabilization, it appears that lithium acts as an inhibitor of kinases that affect phosphorylation of FRQ and other proteins. A competition between Li(+) and Mg(2+) ions for Mg(2+)-binding sites may be a mechanism to how certain kinases are inhibited by Li(+). A possible kinase in this respect is GSK-3, which in other organisms is known to be inhibited by lithium. The partial loss of temperature compensation in the presence of lithium can be understood as an increase in the overall activation energy of FRQ degradation. This increase in activation energy may be related to a reduction in FRQ phosphorylation so that more kinase activity, that is, higher temperature and longer times, is required to achieve the necessary amount of FRQ phosphorylation leading to turnover. Using a modified Goodwin oscillator as a semiquantitative model for the Neurospora clock, the effects of lithium can be described by adding lithium inhibitory terms of FRQ degradation to the model.
|Impaired proteasome activity and accumulation of ubiquitinated substrates in a hereditary neuropathy model. |
Jenny Fortun, Jie Li, Jocelyn Go, Ali Fenstermaker, Bradley S Fletcher, Lucia Notterpek
Journal of neurochemistry 92 1531-41 2005
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Accumulation of misfolded proteins and alterations in the ubiquitin-proteasome pathway are associated with various neurodegenerative conditions of the CNS and PNS. Aggregates containing ubiquitin and peripheral myelin protein 22 (PMP22) have been observed in the Trembler J mouse model of Charcot-Marie-Tooth disease type 1A demyelinating neuropathy. In these nerves, the turnover rate of the newly synthesized PMP22 is reduced, suggesting proteasome impairment. Here we show evidence of proteasome impairment in Trembler J neuropathy samples compared with wild-type, as measured by reduced degradation of substrate reporters. Proteasome impairment correlates with increased levels of polyubiquitinated proteins, including PMP22, and the recruitment of E1, 20S and 11S to aggresomes formed either spontaneously due to the Trembler J mutation or upon proteasome inhibition. Furthermore, myelin basic protein, an endogenous Schwann cell proteasome substrate, associates with PMP22 aggregates in affected nerves. Together, our data show that in neuropathy nerves, reduced proteasome activity is coupled with the accumulation of ubiquitinated substrates, and the recruitment of proteasomal pathway constituents to aggregates. These results provide novel insights into the mechanism by which altered degradation of Schwann cell proteins may contribute to the pathogenesis of certain PMP22 neuropathies.
|20S Proteasome Activity Assay - Data Sheet|