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61.
Patching the gaps in Hedgehog signalling 总被引:2,自引:0,他引:2
The Hedgehog (Hh) pathway plays central roles in animal development and stem-cell function. Defects in Hh signalling lead to birth defects and cancer in humans. The first and often genetically damaged step in this pathway is the interaction between two membrane proteins - Patched (Ptc), encoded by a tumour suppressor gene, and Smoothened (Smo), encoded by a proto-oncogene. Recent work linking Hh signalling to sterol metabolites and protein-trafficking events at the primary cilium promises to shed light on the biochemical basis of how Patched inhibits Smoothened, and to provide new avenues for cancer treatment. 相似文献
62.
Erythrocytes are excellent models for the study of interactions of xenobiotics with biomembranes. Present work is designed to study the in vitro effects of some organophosphates (ethion, chlorpyrifos, dimethoate and monocrotophos) on rat erythrocytes. Treatment of erythrocytes with organophosphates resulted in decreased erythrocyte glucose-6-phosphate dehydrogenase (G-6-PD) activity, whereas activities of glutathione-s-transferase (GST) and glutathione reductase (GR) were increased. Reduced Glutathione (GSH) content of RBCs was decreased after treatment with the pesticides. Increased activities of GST and GR were due to induction of natural defense mechanism of erythrocytes against the toxicity of the pesticides. Membrane bound enzymes like acetylcholinesterase (AChE), Na(+)-K(+)-ATPase and Ca(2+)-ATPase were also inhibited. Altered activities of these enzymes along with decreased GSH content indicate increased oxidative stress in erythrocytes after treatment with organophosphates. 相似文献
63.
Vertebrates produce at least seven distinct β-tubulin isotypes that
coassemble into all cellular microtubules. The functional differences among
these tubulin isoforms are largely unknown, but recent studies indicate that
tubulin composition can affect microtubule properties and cellular
microtubule-dependent behavior. One of the isotypes whose incorporation causes
the largest change in microtubule assembly is β5-tubulin. Overexpression
of this isotype can almost completely destroy the microtubule network, yet it
appears to be required in smaller amounts for normal mitotic progression.
Moderate levels of overexpression can also confer paclitaxel resistance.
Experiments using chimeric constructs and site-directed mutagenesis now
indicate that the hypervariable C-terminal region of β5 plays no role in
these phenotypes. Instead, we demonstrate that two residues found in β5
(Ser-239 and Ser-365) are each sufficient to inhibit microtubule assembly and
confer paclitaxel resistance when introduced into β1-tubulin; yet the
single mutation of residue Ser-239 in β5 eliminates its ability to confer
these phenotypes. Despite the high degree of conservation among β-tubulin
isotypes, mutations affecting residue 365 demonstrate that amino acid
substitutions can be context sensitive; i.e. an amino acid change in
one isotype will not necessarily produce the same phenotype when introduced
into a different isotype. Modeling studies indicate that residue Cys-239 of
β1-tubulin is close to a highly conserved Cys-354 residue suggesting the
possibility that disulfide formation could play a significant role in the
stability of microtubules formed with β1- but not with
β5-tubulin.Microtubules are needed to organize the Golgi apparatus and endoplasmic
reticulum, maintain cell shape, construct ciliary and flagellar axonemes, and
ensure the accurate segregation of genetic material prior to cell division.
These cytoskeletal structures assemble from α- and β-tubulin
heterodimers to form long cylindrical filaments that exist in a state of
dynamic equilibrium characterized by stochastic episodes of slow growth and
rapid shrinkage (1). Impairment
of normal dynamic behavior has serious consequences for cell proliferation and
thus makes microtubules an attractive target for drug development
(2).Vertebrates express multiple β-tubulin genes that produce highly
homologous proteins differing most notably in their C-terminal 15–20
amino acids (3,
4). These variable C-terminal
sequences are conserved across vertebrate species and have been used to
classify β-tubulin genes into distinct isotypes
(5). In mammals, for example,
there are seven known isotypes designated by the numbers I, II, III, IVa, IVb,
V, and VI. The functional significance of the C-terminal sequences is
uncertain, but some studies suggest that they may be involved in binding or
modulating the action of microtubule-interacting proteins
(6–14).
Additional amino acid differences are scattered throughout the primary
sequence, but the functional role of these differences, if any, has not been
elucidated. Although some β-tubulin isotypes are expressed in a
tissue-specific manner (3),
evidence indicates that microtubules incorporate all available isotypes,
including transfected isotypes that are not normally produced in those cells
(5,
15–17).
Genetic experiments designed to test potential functional differences among
the various β-tubulin isotypes have only demonstrated isotype-specific
effects on the assembly of specialized microtubule-containing structures such
as flagellar axonemes in Drosophila or 15-protofilament microtubules
in Caenorhabditis elegans
(18,
19). Thus, the consequences,
if any, of producing multiple β-tubulin isoforms in vertebrate organisms
remain elusive.Our recent work showed that conditional overexpression of isotypes β1,
β2, and β4b has no effect on microtubule assembly or drug
sensitivity in transfected Chinese hamster ovary
(CHO)2 cells
(20). Similarly, expression of
neuronal-specific β4a produced very minor effects on microtubule assembly
but was able to increase sensitivity to paclitaxel, most likely through
increased binding of the drug
(21). On the other hand, high
expression of neuronal-specific β3 reduced microtubule assembly,
conferred low level resistance to paclitaxel, and inhibited cell growth
(22). The most dramatic
effects, however, were seen in cells transfected with β5, a minor but
widely expressed isotype (23).
Even modest overexpression of this isotype reduced microtubule assembly and
conferred paclitaxel resistance, whereas high levels of expression (∼50%
of total tubulin) caused fragmentation and a near complete loss of the
microtubule cytoskeleton (24).
Despite the toxicity associated with β5 overexpression, this isotype was
recently shown to be required for normal mitotic progression and cell
proliferation (25).Because of its importance for cell division, and the extreme phenotype
associated with its overexpression, we sought to identify the structural
differences between β5-tubulin and its more “normal” homolog,
β1. Although there are 40 amino acid differences between the 2 isotypes,
we report that most of the unique properties of β5 can be attributed to
the presence of serine in place of cysteine at residue 239. This residue faces
the colchicine binding pocket and is very close to a highly conserved Cys-354
residue. We propose that Ser-239 found in β5-tubulin may prevent
formation of a disulfide bond that normally stabilizes microtubules. 相似文献
64.
65.
Hubbard VM Valdor R Patel B Singh R Cuervo AM Macian F 《Journal of immunology (Baltimore, Md. : 1950)》2010,185(12):7349-7357
Macroautophagy is a highly conserved mechanism of lysosomal-mediated protein degradation that plays a key role in maintaining cellular homeostasis by recycling amino acids, reducing the amount of damaged proteins, and regulating protein levels in response to extracellular signals. We have found that macroautophagy is induced after effector T cell activation. Engagement of the TCR and CD28 results in enhanced microtubule-associated protein 1 light chain 3 (LC3) processing, increased numbers of LC3-containing vesicles, and increased LC3 flux, indicating active autophagosome formation and clearance. The autophagosomes formed in stimulated T cells actively fuse with lysosomes to degrade their cargo. Using a conditional KO mouse model where Atg7, a critical gene for macroautophagy, is specifically deleted in T cells, we have found that macroautophagy-deficient effector Th cells have defective IL-2 and IFN-γ production and reduced proliferation after stimulation, with no significant increase in apoptosis. We have found that ATP generation is decreased when autophagy is blocked, and defects in activation-induced cytokine production are restored when an exogenous energy source is added to macroautophagy-deficient T cells. Furthermore, we present evidence showing that the nature of the cargo inside autophagic vesicles found in resting T cells differs from the cargo of autophagosomes in activated T cells, where mitochondria and other organelles are selectively excluded. These results suggest that macroautophagy is an actively regulated process in T cells that can be induced in response to TCR engagement to accommodate the bioenergetic requirements of activated T cells. 相似文献
66.
67.
Rajat Sethi Ken S. Dhalla Kanu R. Shah Naranjan S. Dhalla 《Molecular and cellular biochemistry》1993,119(1-2):185-193
Alamethicin is commonly used as an agent for unmasking the latent enzyme activities in vesicular membrane preparations; however, relatively little is known about the effect of this agent on the characteristics of adenylyl cyclase in heart sarcolemma. By employing rat heart sarcolemmal preparation, we observed 5 to 6 fold increase in adenylyl cyclase activity upon treatment with alamethicin. Kinetic experiments using various concentrations of MgATP revealed that the increase in adenylyl cyclase activity in alamethicin treated membranes was associated with an increase in Vmax as well as affinity of the substrate for the enzyme. Dose-responses of the control and alamethicin-treated preparations to various activators of adenylyl cyclase revealed that the sensitivity of the enzyme to forskolin, NaF and GppNHp, was markedly increased upon treating sarcolemma with alamethicin. The activation of adenylyl cyclase by forskolin was also enhanced by increasing the concentration of alamethicin in the incubation medium. Furthermore, there was a greater increase in adenylyl cyclase activity with different concentrations of Mn2+ in the presence of alamethicin. These results suggest that alamethicin treatment alters the characteristics of adenylyl cyclase in addition to unmasking the enzyme activity in the purified sarcolemmal vesicular preparation. 相似文献
68.
Vaclav Pelouch Ian M. C. Dixon Rajat Sethi Naranjan S. Dhalla 《Molecular and cellular biochemistry》1993,129(2):121-131
The rat model of myocardial infarction is characterized by progressive cardiac hypertrophy and failure. Rats with infarcts greater than 30% of the left ventricle exhibited early and moderate, stages of heart failure 4 and 8 weeks after the occlusion of the left coronary artery, respectively. As heart failure is usually associated with remodeling of the extracellular matrix, a histological and biochemical study of cardiac collagenous proteins was carried out using failing hearts. Total collagen content in the right ventricle increased at 2, 4, and 8 weeks following occlusion of the left coronary artery whereas such a change in viable left ventricle was seen after 4 and 8 weeks. Total cardiac hydroxyproline concentration was increased in both right and left ventricular samples from the infarcted animals when compared to those of control; this increase was due to elevation of pepsin-insoluble collagen fraction. The myocardial noncollagenous/collagenous protein ratio was decreased in experimental right and left ventricular samples when compared to control samples. These findings suggest that an increase in cross-linking of cardiac collagen as well as disparate synthesis of collagenous and noncollagenous proteins occurs in this model of congestive heart, failure. 相似文献
69.
Reduced expressions of calmodulin genes and protein and reduced ability of calmodulin to activate plasma membrane Ca2+‐ATPase in the brain of protein undernourished rats: modulatory roles of selenium and zinc supplementation
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Olusegun L. Adebayo Alka Khera Rajat Sandhir Gbenga A. Adenuga 《Cell biochemistry and function》2016,34(2):95-103
The roles of protein undernutrition as well as selenium (Se) and zinc (Zn) supplementation on the ability of calmodulin (CaM) to activate erythrocyte ghost membrane (EGM) Ca2+‐ATPase and the calmodulin genes and protein expressions in rat's cortex and cerebellum were investigated. Rats on adequate protein diet and protein‐undernourished (PU) rats were fed with diet containing 16% and 5% casein, respectively, for a period of 10 weeks. The rats were then supplemented with Se and Zn at a concentration of 0.15 and 227 mg l−1, respectively, in drinking water for 3 weeks. The results obtained from the study showed significant reductions in synaptosomal plasma membrane Ca2+‐ATPase (PMCA) activity, Ca2+/CaM activated EGM Ca2+ATPase activity and calmodulin genes and protein expressions in PU rats. Se or Zn supplementation improved the ability of Ca2+/CaM to activate EGM Ca2+‐ATPase and protein expressions. Se or Zn supplementation improved gene expression in the cerebellum but not in the cortex. Also, the activity of PMCA was significantly improved by Zn. In conclusion, it is postulated that Se and Zn might be beneficial antioxidants in protecting against neuronal dysfunction resulting from reduced level of calmodulin such as present in protein undernutrition. Copyright © 2016 John Wiley & Sons, Ltd. 相似文献
70.
Sethi Rajat Shao Qiming Ren Bin Saini Harjot K. Takeda Nobuakira Dhalla Naranjan S. 《Molecular and cellular biochemistry》2004,263(1):11-20
Earlier studies have revealed an improvement of cardiac function in animals with congestive heart failure (CHF) due to myocardial infarction (MI) by treatment with angiotensin converting enzyme (ACE) inhibitors. Since heart failure is also associated with attenuated responses to catecholamines, we examined the effects of imidapril, an ACE inhibitor, on the -adrenoceptor (-AR) signal transduction in the failing heart. Heart failure in rats was induced by occluding the coronary artery, and 3 weeks later the animals were treated with 1 mg/(kg·day) (orally) imidapril for 4 weeks. The animals were assessed for their left ventricular function and inotropic responses to isoproterenol. Cardiomyocytes and crude membranes were isolated from the non-ischemic viable left ventricle and examined for the intracellular concentration of Ca2+ [Ca2+]i and -ARs as well as adenylyl cyclase (AC) activity, respectively. Animals with heart failure exhibited depressions in ventricular function and positive inotropic response to isoproterenol as well as isoproterenol-induced increase in [Ca2+]i in cardiomyocytes; these changes were attenuated by imidapril treatment. Both 1-AR receptor density and isoproterenol-stimulated AC activity were decreased in the failing heart and these alterations were prevented by imidapril treatment. Alterations in cardiac function, positive inotropic effect of isoproterenol, 1-AR density and isoproterenol-stimulated AC activity in the failing heart were also attenuated by treatment with another ACE inhibitor, enalapril and an angiotensin II receptor antagonist, losartan. The results indicate that imidapril not only attenuates cardiac dysfunction but also prevents changes in -AR signal transduction in CHF due to MI. These beneficial effects are similar to those of enalapril or losartan and thus appear to be due to blockade of the renin–angiotensin system. (Mol Cell Biochem 263: 11–20, 2004) 相似文献