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1.
Oshima T Sasaki M Kataoka H Miwa H Takeuchi T Joh T 《Cellular and molecular life sciences : CMLS》2007,64(23):3139-3147
Tight junctions (TJs) create a paracellular permeability barrier. Although reactive oxygen species have been implicated as
mediators of inflammation in inflammatory bowel diseases, their influence on the function of colonic epithelial TJs remains
unknown. Oxidative stress-mediated colonic epithelial permeability was significantly attenuated by a p38 mitogen-activated
protein (MAP) kinase inhibitor, SB203580. Although the amount of TJ proteins was not altered, hydrogen peroxide (H2O2) changed the localization of claudin-4 protein from an NP-40 insoluble fraction to a soluble fraction and from an apical
TJ to lateral membrane. The p38 MAP kinase inactivator Wip1 significantly attenuated phosphorylation of p38 MAP kinase, and
oxidative stress mediated permeability. H2O2-induced changes in claudin-4 localization were abolished by SB203580 pretreatment as well as Wip1-expressing adenovirus infection.
This is the first study to demonstrate that exogenous Wip1 functions to protect oxidative stress-mediated colonic mucosal
permeability and that H2O2-induced claudin-4 dislocalization is abolished by Wip1.
Received 14 June 2007; received after revision 8 October 2007; accepted 8 October 2007 相似文献
2.
Signalling roles of mammalian phospholipase D1 and D2 总被引:11,自引:0,他引:11
S. Cockcroft 《Cellular and molecular life sciences : CMLS》2001,58(11):1674-1687
Phospholipase D (PLD) catalyses the hydrolysis of phosphatidylcholine to generate the lipid second messenger, phosphatidate
(PA) and choline. PLD activity in mammalian cells is low and is transiently stimulated upon activation by G-protein-coupled
and receptor tyrosine kinase cell surface receptors. Two mammalian PLD enzymes (PLD1 and PLD2) have been cloned and their
intracellular regulators identified as ARF and Rho proteins, protein kinase Cα as well as the lipid, phosphatidylinositol
[4, 5] bisphosphate (PIP2). I discuss the regulation of these enzymes by cell surface receptors, their cellular localisation and the potential function
of PA as a second messenger. Evidence is presented for a role of PA in regulating the lipid kinase activity of PIP 5-kinase,
an enzyme that synthesises PIP2. A signalling role of phospholipase D via PA and indirectly via PIP2 in regulating membrane traffic and actin dynamics is indicated by the available data.
Received 25 April 2001; received after revision 15 June 2001; accepted 15 June 2001 相似文献
3.
Hydrogen peroxide protects tobacco from oxidative stress by inducing a set of antioxidant enzymes 总被引:13,自引:0,他引:13
Gechev T Gadjev I Van Breusegem F Inzé D Dukiandjiev S Toneva V Minkov I 《Cellular and molecular life sciences : CMLS》2002,59(4):708-714
Tolerance against oxidative stress generated by high light intensities or the catalase inhibitor aminotriazole (AT) was induced
in intact tobacco plants by spraying them with hydrogen peroxide (H2O2). Stress tolerance was concomitant with an enhanced antioxidant status as reflected by higher activity and/or protein levels
of catalase, ascorbate peroxidase, guaiacol peroxidases, and glutathione peroxidase, as well as an increased glutathione pool.
The induced stress tolerance was dependent on the dose of H2O2 applied. Moderate doses of H2O2 enhanced the antioxidant status and induced stress tolerance, while higher concentrations caused oxidative stress and symptoms
resembling a hypersensitive response. In stress-tolerant plants, induction of catalase was 1.5-fold, that of ascorbate peroxidase
and glutathione peroxidase was 2-fold, and that of guaiacol peroxidases was approximately 3-fold. Stress resistance was monitored
by measuring levels of malondialdehyde, an indicator of lipid peroxidation. The levels of malondialdehyde in all H2O2-treated plants exposed to subsequent high light or AT stress were similar to those of unstressed plants, whereas lipid peroxidation
in H2O2-untreated plants stressed with either high light or AT was 1.5- or 2-fold higher, respectively. Although all stress factors
caused increases in the levels of reduced glutathione, its levels were much higher in all H2O2-pretreated plants. Moreover, significant accumulation of oxidized glutathione was observed only in plants that were not pretreated
with H2O2. Extending the AT stress period from 1 to 7 days resulted in death of tobacco plants that were not pretreated with H2O2, while all H2O2-pretreated plants remained little affected by the prolonged treatment. Thus, activation of the plant antioxidant system by
H2O2 plays an important role in the induced tolerance against oxidative stress.
Received 11 December 2001; received after revision 25 January 2002; accepted 4 February 2002 相似文献
4.
Effects of myocardial ischemia and reperfusion on mitochondrial function and susceptibility to oxidative stress 总被引:8,自引:0,他引:8
We investigated the effects of ischemia duration on the functional response of mitochondria to reperfusion and its relationship
with changes in mitochondrial susceptibility to oxidative stress. Mitochondria were isolated from hearts perfused by the Langendorff
technique immediately after different periods of global ischemia or reperfusion following such ischemia periods. Rates of
O2 consumption and H2O2 release with complex I- and complex II-linked substrates, lipid peroxidation, overall antioxidant capacity, capacity to remove
H2O2, and susceptibility to oxidative stress were determined. The effects of ischemia on some parameters were time dependent so
that the changes were greater after 45 than after 20 min of ischemia, or were significantly different to the nonischemic control
only after 45 min of ischemia. Thus, succinate-supported state 3 respiration exhibited a significant decrease after 20 min
of ischemia and a greater decrease after 45 min, while pyruvate malate-supported respiration showed a significant decrease
only after 45 min of ischemia, indicating an ischemia-induced early inhibition of complex II and a late inhibition of complex
I. Furthermore, both succinate and pyruvate malate-supported H2O2 release showed significant increases only after 45 min of ischemia. Similarly, whole antioxidant capacity significantly increased
and susceptibility to oxidants significantly decreased after 45 min of ischemia. Such changes were likely due to the accumulation
of reducing equivalents, which are able to remove peroxides and maintain thiols in a reduced state. This condition, which
protects mitochondria against oxidants, increases mitochondrial production of oxyradicals and oxidative damage during reperfusion.
This could explain the smaller functional recovery of the tissue and the further decline of the mitochondrial function after
reperfusion following the longer period of oxygen deprivation.
Received 18 May 2001; received after revision 17 July 2001; accepted 24 July 2001 相似文献
5.
Oxidative stress and hypoxia-like injury cause Alzheimer-type molecular abnormalities in central nervous system neurons 总被引:11,自引:0,他引:11
de la Monte SM Neely TR Cannon J Wands JR 《Cellular and molecular life sciences : CMLS》2000,57(10):1471-1481
Neuronal loss and neuritic/cytoskeletal lesions (synaptic disconnection and proliferation of dystrophic neurites) represent
major dementia-associated abnormalities in Alzheimer’s disease (AD). This study examined the role of oxidative stress as a
factor contributing to both the cell death and neuritic degeneration cascades in AD. Primary neuron cultures were treated
with H2O2 (9–90 μM) or desferrioxamine (2–25 μM) for 24 h and then analyzed for viability, mitochondrial mass, mitochondrial function,
and pro-apoptosis and sprouting gene expression. H2O2 treatment causes free-radical injury and desferrioxamine causes hypoxia-type injury without free radical generation. The
H2O2-treated cells exhibited sustained viability but neurite retraction, impaired mitochondrial function, increased levels of
the pro-apoptosis gene product CD95/Fas, reduced expression of N2J1-immunoreactive neuronal thread protein and synaptophysin,
and reduced distribution of mitochondria in neuritic processes. Desferrioxamine treatment resulted in dose-dependent neuronal
loss associated with impaired mitochondrial function, proliferation of neurites, and reduced expression of GAP-43, which has
a role in path-finding during neurite outgrowth. The results suggest that oxidative stress can cause neurodegeneration associated
with enhanced susceptibility to apoptosis due to activation of pro-apoptosis genes, neurite retraction (synaptic disconnection),
and impaired transport of mitochondria to cell processes where they are likely required for synaptic function. In contrast,
hypoxia-type injury causes neuronal loss with proliferation of neurites (sprouting), impaired mitochondrial function, and
reduced expression of molecules required to form and maintain synaptic connections. Since similar abnormalities occur in AD,
both oxidative stress and hypoxic injury can contribute to AD neurodegeneration.
Received 24 May 2000; received after revision 7 July 2000; accepted 27 July 2000 相似文献
6.
Culture in low levels of oxygen enhances in vitro proliferation potential of satellite cells from old skeletal muscles 总被引:4,自引:0,他引:4
Chakravarthy MV Spangenburg EE Booth FW 《Cellular and molecular life sciences : CMLS》2001,58(8):1150-1158
The proliferation ability of satellite cells (considered the 'stem cells' of mature myofibers) declines with increasing age
when cultured under standard cell culture conditions of 21% oxygen. However, actual oxygen levels in the intact myofiber in
vivo are an order of magnitude lower. No studies to date have addressed the issue of whether culturing satellite cells from
old muscles under more 'physiologic' conditions would enhance their proliferation and/or differentiation ability. Therefore,
we analyzed satellite cells derived from 31-month-old rats in standard cultures with 21% O2 and in lowered (∼3%) O2. Under the lowered O2 conditions, we noted a remarkable increase in the percentage of large-sized colonies, activation of cell cycle progression
factors, phosphorylation of Akt, and downregulation of the cell cycle inhibitor p27Kip1. These data suggest that lower O2 levels provide a milieu that stimulates proliferation by allowing continued cell cycle progression, to result ultimately
in the enhanced in vitro replicative life span of the old satellite cells. Such a method therefore provides an improved means
for the ex vivo generation of progenitor satellite cell populations for potential therapeutic stem cell transplantation.
Received 20 April 2001; received after revision 28 May 2001; accepted 31 May 2001 相似文献
7.
J. W. M. Lagerberg J. VanSteveninck T. M. A. R. Dubbelman 《Cellular and molecular life sciences : CMLS》1997,53(3):257-262
The fluorescent dye Merocyanine 540 (MC540) is often used as a probe to monitor the molecular packing of phospholipids in
the outer leaflet of biomembranes. In a previous study we showed that the increased staining of erythrocytes with a perturbed
membrane structure was mainly due to an increase in the fluorescence yield of cell-bound MC540, rather than to an increase
of the number of bound molecules. Erythrocytes and ghosts exposed to continuous fluxes of H2O2 exhibited pronounced lipid peroxidation. Further, red blood cells subjected to this form of oxidative stress also showed
increased staining with MC540. It appeared that this was caused by a strong increase in binding of MC540, together with a
slight red shift of the fluorescence emission maximum and a small increase in the fluorescence yield of bound MC540. The changed
MC540 binding characteristics were not observed when lipid peroxidation was suppressed by the presence of the antioxidant
BHT in the incubation medium. However, open ghosts exposed to H2O2 showed no increase of MC540 binding, excluding a direct involvement of lipid peroxidation. Measurement of fluorescence emission
spectra and gel filtration studies showed that MC540 can bind to H2O2-exposed hemoglobin. Experiments with erythrocytes lysed in hypotonic medium after exposure to H2O2 revealed that peroxidation of lipids with H2O2 induced a non-specific permeabilization of the plasma membrane to MC540, thereby allowing MC540 to bind to the oxidatively
denatured, more hydrophobic hemoglobin. These results indicate that conclusions about packing of phospholipids in the outer
leaflet of the membrane based on increased MC540-staining should be drawn with care.
Received 27 September 1996; received after revision 5 November 1996; accepted 27 November 1996 相似文献
8.
Identification of tyrosine-phosphorylated proteins of the mitochondrial oxidative phosphorylation machinery 总被引:1,自引:1,他引:0
Augereau O Claverol S Boudes N Basurko MJ Bonneu M Rossignol R Mazat JP Letellier T Dachary-Prigent J 《Cellular and molecular life sciences : CMLS》2005,62(13):1478-1488
The role of some serine/threonine kinases in the regulation of mitochondrial physiology is now well established, but little is known about mitochondrial tyrosine kinases. We showed that tyrosine phosphorylation of rat brain mitochondrial proteins was increased by in vitro addition of ATP and H2O2, and also during in situ ATP production at state 3, and maximal reactive oxygen species production. The Src kinase inhibitor PP2 decreased tyrosine phosphorylation and respiratory rates at state 3. We found that the 39-kDa subunit of complex I was tyrosine phosphorylated, and we identified putative tyrosine-phosphorylated subunits for the other complexes. We also have strong evidence that the FoF1-ATP synthase α chain is probably tyrosine-phosphorylated, but demonstrated that the β chain is not. The tyrosine phosphatase PTP 1B was found in brain but not in muscle, heart or liver mitochondria. Our results suggest that tyrosine kinases and phosphatases are involved in the regulation of oxidative phosphorylation.Received 7 January 2005; received after revision 19 April 2005; accepted 22 April 2005 相似文献
9.
Bryja V Pacherník J Soucek K Horvath V Dvorák P Hampl A 《Cellular and molecular life sciences : CMLS》2004,61(11):1384-1400
In mouse embryonic stem (mES) cells, the expression of p27 is elevated when differentiation is induced. Using mES cells lacking p27 we tested the importance of p27 for the regulation of three critical cellular processes: proliferation, differentiation, and apoptosis. Although cell cycle distribution, DNA synthesis, and the activity of key G1/S-regulating cyclin-dependent kinases remained unaltered in p27-deficient ES cells during retinoic acid-induced differentiation, the amounts of cyclin D2 and D3 in such cells were much lower compared with normal mES cells. The onset of differentiation induces apoptosis in p27-deficient cells, the extent of which can be reduced by artificially increasing the level of cyclin D3. We suggest that the role of p27 in at least some differentiation pathways of mES cells is to prevent apoptosis, and that it is not involved in slowing cell cycle progression. We also propose that the pro-survival function of p27 is realized via regulation of metabolism of D-type cyclin(s).Received 25 February 2004; received after revision 5 April 2004; accepted 15 April 2004 相似文献
10.
Rivera A Mavila A Bayless KJ Davis GE Maxwell SA 《Cellular and molecular life sciences : CMLS》2006,63(12):1425-1439
We were the first to identify cyclin A1 as a p53-induced gene by cDNA expression profiling of p53-sensitive and -resistant
tumor cells [Maxwell S. A. and Davis G. E. (2000) Proc. Natl. Acad. Sci. USA 97, 13009–13014]. We show here that cyclin A1
can induce G2 cell cycle arrest, polyploidy, apoptosis, and mitotic catastrophe in H1299 non-small cell lung, TOV-21G ovarian,
or 786-0 renal carcinoma cells. More cdk1 protein and kinase activities were observed in cyclin A1-induced cells than in GFP
control-induced cells. Thus, cyclin A1 might mediate apoptosis and mitotic catastrophe through an unscheduled or inappropriate
activation of cdk1. Two primary renal cell carcinomas expressing mutated p53 exhibited reduced or absent expression of cyclin
A1 relative to the corresponding normal tissue. Moreover, renal carcinoma-derived mutant p53s were deficient in inducing cyclin
A1 expression in p53-null cells. Cyclin A1 but not cyclin A2 was upregulated in etoposide-treated tumor cells undergoing p53-dependent
apoptosis and mitotic catastrophe. Forced upregulation of cyclin A2 did not induce apoptosis. The data implicate cyclin A1
as a downstream player in p53-dependent apoptosis and G2 arrest.
Received 1 November 2005; received after revision 17 February 2006; accepted 13 April 2006 相似文献
11.
Higgins GC Devenish RJ Beart PM Nagley P 《Cellular and molecular life sciences : CMLS》2011,68(22):3725-3740
Primary neurons undergo insult-dependent programmed cell death. We examined autophagy as a process contributing to cell death
in cortical neurons after treatment with either hydrogen peroxide (H2O2) or staurosporine. Although caspase-9 activation and cleavage of procaspase-3 were significant following staurosporine treatment,
neither was observed following H2O2 treatment, indicating a non-apoptotic death. Autophagic activity increased rapidly with H2O2, but slowly with staurosporine, as quantified by processing of endogenous LC3. Autophagic induction by both stressors increased
the abundance of fluorescent puncta formed by GFP-LC3, which could be blocked by 3-methyladenine. Significantly, such inhibition
of autophagy blocked cell death induced by H2O2 but not staurosporine. Suppression of Atg7 inhibited cell death by H2O2, but not staurosporine, whereas suppression of Beclin 1 prevented cell death by both treatments, suggesting it has a complex
role regulating both apoptosis and autophagy. We conclude that autophagic mechanisms are activated in an insult-dependent
manner and that H2O2 induces autophagic cell death. 相似文献
12.
The sensitivity ofDeleya halophila to oxidative stress caused by hydrogen peroxide (H2O2) was found to vary, depending on the NaCl concentration of the growth medium. Pretreatment of the bacteria at a low concentration of H2O2 (50 M) protected the cells against the lethal effects of higher levels (1–2 mM) of H2O2. Exposure ofD. halophila cells to 50 M H2O2 resulted in the induction of several proteins (hydrogen peroxide-inducible proteins, hips). However, the kinetics of induction, the extent of induction and the number of hips appear to be influenced by the salt concentration of the growth medium. Five of the hips exhibited apparent molecular masses identical to those of five heat shock proteins (hsps). 相似文献
13.
Larsson LI 《Cellular and molecular life sciences : CMLS》2004,61(19-20):2624-2631
Binding of growth factors to cell surface receptors activates protein tyrosine kinases (PTKs) that initiate cascades of downstream signaling events including the mitogen-activated protein (MAP) kinase cascade. This study reports that the PTK inhibitor AG 879 inhibits proliferation of human breast cancer cells through an effect involving inhibition of MAP kinase activation, but which cannot be explained by effects of AG 879 on its known PTK targets. Instead, AG 879 markedly inhibits expression of the RAF-1 gene, which encodes an upstream MAP kinase kinase kinase. Additionally, expression of HER-2, but not of other genes tested, is inhibited by this compound. These novel effects have to be considered when using AG 879 as a TRK-A and HER-2 inhibitor but may have useful therapeutic implications. 相似文献
14.
Gavin C. Higgins Philip M. Beart Phillip Nagley 《Cellular and molecular life sciences : CMLS》2009,66(16):2773-2787
To characterize neuronal death, primary cortical neurons (C57/Black 6 J mice) were exposed to hydrogen peroxide (H2O2) and staurosporine. Both caused cell shrinkage, nuclear condensation, DNA fragmentation and loss of plasma membrane integrity.
Neither treatment induced caspase-7 activity, but caspase-3 was activated by staurosporine but not H2O2. Each treatment caused redistribution from mitochondria of both endonuclease G (Endo G) and cytochrome c. Neurons knocked down for Endo G expression using siRNA showed reduction in both nuclear condensation and DNA fragmentation
after treatment with H2O2, but not staurosporine. Endo G suppression protected cells against H2O2-induced cell death, while staurosporine-induced death was merely delayed. We conclude that staurosporine induces apoptosis
in these neurons, but severe oxidative stress leads to Endo G-dependent death, in the absence of caspase activation (programmed
cell death-type III). Therefore, oxidative stress triggers in neurons a form of necrosis that is a systematic cellular response
subject to molecular regulation.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
15.
Summary Homogenates from T. cruzi epimastigotes produced 3.4 pmoles H2O2/min 106 cells, as detected by the cytochrome c peroxidase assay. Addition of NADH or NADPH increased H2O2 production by a factor of 3 and 5, respectively. When supplemented with NADH and NADPH, the mitochondrial, microsomal, and supernatant fractions produced H2O2, the soluble fraction and the mitochondrial membranes being apparently the main generators of H2O2. The epimastigote homogenates showed cyanide-sensitive superoxide dismutase activity, equivalent to 0.28 g bovine superoxide dismutase per mg homogenate protein.This investigation was supported by grants from Consejo Nacional de Investigaciones Cientificas y Técnicas (CONICET) Argentina and the Scientific Office, American States Organization.Career Investigator of CONICET. 相似文献
16.
Summary DCP increases IAA destruction by bothLens andPhaseolus root breis. H2O2 inhibits catabolism byLens extracts but activates it whenPhaseolus is used, mainly when roots are cultivated in the dark and contain inhibitors of IAA destruction. DCP 1·10–3
M and H2O2 1·10–4 or 1·10–3 volume forLens and DCP 1·10–4
M and H2O2 1·10–3 volume forPhaseolus nullify auxin catabolism. 相似文献
17.
C. Nations R. G. Allen K. J. Farmer P. L. Toy R. S. Sohal 《Cellular and molecular life sciences : CMLS》1986,42(1):64-66
Summary Superoxide dismutase activity was slow throughout the cell cycle of surface cultures ofPhysarum polycephalum. This activity increased markedly when the organism was induced to spherulate. Glutathione (GSH) and hydrogen peroxide (H2O2) concentrations changed very little during the cell cycle. During spherulation GSH decreased; H2O2 and the cyanide-resistant respiration of plasmodial homogenates increased. 相似文献
18.
Rose P Whiteman M Huang SH Halliwell B Ong CN 《Cellular and molecular life sciences : CMLS》2003,60(7):1489-1503
-Phenylethyl isothiocyanate (PEITC) is a promising chemoprotective compound that is
routinely consumed in the diet as its glucosinolate precursor. Previous studies have shown that PEITC
can inhibit phase I enzymes and induce phase II detoxification enzymes along with apoptosis in vitro.
The detailed mechanisms involved in the apoptotic cascade, however, have not been elucidated. In the
present study, we demonstrate that PEITC can induce apoptosis in hepatoma HepG2 cells in a
concentration- and time-dependant manner as determined by TUNEL positive and SubG1 population
analysis. Caspase-3-like activity and poly(ADP-ribosyl)polymerase cleavage increased during
treatment with 20 µM PEITC; high concentrations, however, induced necrosis. Pre-treatment with
Z-VAD-FMK and the caspase-3-specific inhibitor Ac-DEVD-CHO prevented PEITC-induced apoptosis, as
determined by caspase-3-like activity and DNA fragmentation. Additional investigations also showed
that at concentrations of 5-C10 µM PEITC, DNA synthesis was inhibited and G2/M phase cell cycle
arrest occurred, correlating with an alteration in cyclin B1 and p34cdc2 protein levels. Furthermore, we also demonstrate
a concentration- and time-dependant burst of superoxide (O2-)
in PEITC-treated cells. However, pre- and co-treatment with the free radical scavengers Trolox,
ascorbate, mannitol, uric acid and the superoxide mimetic manganese (III) tetrakis (N-methyl-2-pyridyl)
porphyrin failed to prevent PEITC-mediated apoptosis. Taken together, these results suggest that
PEITC potently induces apoptosis and cell cycle arrest in HepG2 cells and that the
generation of reactive oxygen species appears to be a secondary effect.Received 23 December 2002; accepted 22 April 2003 相似文献
19.
Elevated levels of butyrylcholinesterase activity occur under a number of hypertriglyceridemic conditions, including diabetes
and obesity. This study examines whether butyrylcholinesterase activity has a direct effect on triglyceride production, using
Caco-2 cells, a human intestinal adenocarcinoma cell line. Caco-2 cells were incubated with 500 μM oleate to stimulate triglyceride
production, and butyrylcholinesterase activity was measured in the cellular homogenate. Butyrylcholinesterase activity was
approximately 3 × 10-3 mmol/min per milligram protein. Although triglyceride production increased by almost five-fold after 18 h of stimulation
with oleate, butyrylcholinesterase activity was not increased. Furthermore, inhibition of butyrylcholinesterase activity using
1 mM tetraisopropylpyrophosphoramide did not significantly affect triglyceride production or secretion. Human insulin (100
μU/ml) increased the production of butyrylcholinesterase without increasing triglyceride production. This demonstrates that
stimulation of fatty acid production and butyrylcholinesterase activity occur by independent mechanisms and suggests that
their correlation in hyperlipidemic conditions is not due to a direct relationship in production in situ.
Received 23 April 2001; received after revision 25 May 2001; accepted 20 June 2001 相似文献
20.
Shachi P. Patel Suzanne J. Randle Sarah Gibbs Anne Cooke Heike Laman 《Cellular and molecular life sciences : CMLS》2017,74(8):1553-1566
G1 phase cell cycle proteins, such as cyclin-dependent kinase 6 (Cdk6) and its activating partners, the D-type cyclins, are important regulators of T-cell development and function. An F-box protein, called F-box only protein 7 (Fbxo7), acts as a cell cycle regulator by enhancing cyclin D-Cdk6 complex formation and stabilising levels of p27, a cyclin-dependent kinase inhibitor. We generated a murine model of reduced Fbxo7 expression to test its physiological role in multiple tissues and found that these mice displayed a pronounced thymic hypoplasia. Further analysis revealed that Fbxo7 differentially affected proliferation and apoptosis of thymocytes at various stages of differentiation in the thymus and also mature T-cell function and proliferation in the periphery. Paradoxically, Fbxo7-deficient immature thymocytes failed to undergo expansion in the thymus due to a lack of Cdk6 activity, while mature T cells showed enhanced proliferative capacity upon T-cell receptor engagement due to reduced p27 levels. Our studies reveal differential cell cycle regulation by Fbxo7 at different stages in T-cell development. 相似文献