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83.
Morgillo F Bareschino MA Bianco R Tortora G Ciardiello F 《Differentiation; research in biological diversity》2007,75(9):788-799
In recent years, the epidermal growth factor receptor (EGFR) has been recognized as a central player and regulator of cancer cell proliferation, apoptosis and angiogenesis and, therefore, as a potentially relevant therapeutic target. Several strategies for EGFR targeting have been developed, the most succesful being represented by monoclonal antibodies, that directly interfere with ligand-receptor binding and small molecule tyrosine kinase inhibitors, that interfere with activation/phosphorylation of EGFR. These agents have been authorized in advanced chemorefractory cancers, including colorectal cancer, non-small-cell lung cancer and head and neck cancer. However, evidence of resistance to these drugs has been described and extensive studies have been performed to investigate whether resistance to EGFR-targeted therapy is primary or secondary. Cellular levels of EGFR do not always correlate with response to the EGFR inhibitors. Indeed, in spite of the over expression and efficient inhibition of EGFR, resistance to EGFR inhibitors may occur. Moreover, given the genetic instability of cancer cells, genetic modifications could enable them to acquire a resistant phenotype to anti-EGFR therapies. Taken together, these findings support the importance of understanding the molecular mechanisms affecting cancer cell sensitivity or resistance to such inhibitors. This review will focus on the most relevant mechanisms contributing to the acquisition of sensitivity/resistance to EGFR inhibitors. 相似文献
84.
Loreto F Centritto M Barta C Calfapietra C Fares S Monson RK 《Plant, cell & environment》2007,30(5):662-669
In past studies, it was hypothesized that reductions in chloroplast isoprene emissions at high atmospheric CO(2) concentrations were caused by competition between cytosolic and mitochondrial processes for the same substrate, possibly phosphoenolpyruvate (PEP). We conducted field and laboratory experiments using leaves of white poplar (Populus alba L.) to identify whether an inverse relationship occurs between the dark respiration rate (a mitochondrial process) and the isoprene emission rate. Field experiments that were carried out in a free-air CO(2)-enriched (FACE) facility showed no clear effect of elevated CO(2) on either isoprene emission rate or respiration rate by leaves. In young, not yet fully expanded leaves, low isoprene emission and high dark respiration rates were measured in both ambient and elevated CO(2). In these leaves, isoprene emission was inversely correlated with dark respiration. It is possible to interpret from these results that, in young leaves, high rates of growth respiration compete with isoprene biosynthesis for the same substrate. However, it is also possible that the negative correlation reflects the contrasting reductions in growth respiration and increases in expression of the enzyme isoprene synthase at this final stage of leaf maturation. In contrast to our observations on young leaves, respiration rate and isoprene emission rate were positively correlated in older, fully expanded leaves (8 and 11 from apex). A positive correlation was also found between respiration rate and isoprene emission rate when these parameters were modulated using different ozone exposure, growth light intensity, growth temperature and exposure to different leaf temperatures in laboratory experiments. These data show that competition for substrate between isoprene biosynthesis and leaf respiration does not determine the rate of isoprene emission in most circumstances that affect both processes. A negative correlation was observed across all experiments between isoprene emission rate and the activity of phosphoenolpyruvate carboxylase (PEPc), a cytosolic enzyme that competes with isoprene biosynthesis for substrate. The cytosolic metabolite, PEP, occurs at a metabolic branch point from which substrate flows into three processes: (1) the production of pyruvate for mitochondrial respiration, (2) the production of oxaloacetate (OAA) by PEPc for anabolic support of mitochondrial respiration and (3) transport into the chloroplast to support chloroplastic demands for pyruvate, including isoprenoid biosynthesis. The results of our observations suggest that only the second process competes for substrate with isoprenoid synthesis, while the partitioning of PEP between mitochondrial respiration and chloroplast isoprenoid biosynthesis is controlled in a way that retains balance in substrate demand. 相似文献
85.
Properties and exploitation of oleosins 总被引:3,自引:0,他引:3
Oleosins stabilize oil bodies in seeds and other tissues and contain a unique hydrophobic domain which appears to be inserted into the oil matrix as an alpha-helical hairpin. The oleosin proteins may be exploited to stabilize emulsions while the ease of oil body preparation has led to the expression of bioactive proteins as oleosin fusions in molecular farming. 相似文献
86.
Maria Teresa Gentile Claudia Ciniglia Mafalda G. Reccia Floriana Volpicelli Monica Gatti Stefano Thellung Tullio Florio Mariarosa A. B. Melone Luca Colucci-D’Amato 《PloS one》2015,10(3)
Glioblastoma multiforme is a highly aggressive brain tumor whose prognosis is very poor. Due to early invasion of brain parenchyma, its complete surgical removal is nearly impossible, and even after aggressive combined treatment (association of surgery and chemo- and radio-therapy) five-year survival is only about 10%. Natural products are sources of novel compounds endowed with therapeutic properties in many human diseases, including cancer. Here, we report that the water extract of Ruta graveolens L., commonly known as rue, induces death in different glioblastoma cell lines (U87MG, C6 and U138) widely used to test novel drugs in preclinical studies. Ruta graveolens’ effect was mediated by ERK1/2 and AKT activation, and the inhibition of these pathways, via PD98058 and wortmannin, reverted its antiproliferative activity. Rue extract also affects survival of neural precursor cells (A1) obtained from embryonic mouse CNS. As in the case of glioma cells, rue stimulates the activation of ERK1/2 and AKT in A1 cells, whereas their blockade by pharmacological inhibitors prevents cell death. Interestingly, upon induction of differentiation and cell cycle exit, A1 cells become resistant to rue’s noxious effects but not to those of temozolomide and cisplatin, two alkylating agents widely used in glioblastoma therapy. Finally, rutin, a major component of the Ruta graveolens water extract, failed to cause cell death, suggesting that rutin by itself is not responsible for the observed effects. In conclusion, we report that rue extracts induce glioma cell death, discriminating between proliferating/undifferentiated and non-proliferating/differentiated neurons. Thus, it can be a promising tool to isolate novel drugs and also to discover targets for therapeutic intervention. 相似文献
87.
Rosella Colonna Carla Tatone Antonella Francione Floriana Rosati Giuliano Callaini Daniela Corda Luisella Di Francesco 《Molecular reproduction and development》1997,48(2):292-299
The aim of the present study was to investigate the implication of protein kinase C (PKC) in the mouse egg activation process. We used OAG (1-oleoyl-2-acetyl-sn-glycerol) as a PKC activator, calphostin C as a specific PKC inhibitor, and the calcium ionophore A23187 as a standard parthenogenetic agent. The exposure of zona-free eggs to 150 μM or 50 μM OAG for 10 min resulted in meiosis II completion in ∼80% of instances. By contrast, at a lower concentration (25 μM), the PKC stimulator was ineffective as parthenogenetic agent. Shortly after the application of 150 μM OAG, the cytosolic Ca2+ concentration ([Ca2+]i) increased transiently in all the eggs examined, whereas after the addition of 50 μM OAG, [Ca2+]i remained unchanged for at least 20 min. During this period, the activity of M-phase promoting factor (MPF) dramatically decreased and most of the eggs entered anaphase except when the PKC was inhibited by calphostin C. Similarly, MPF inactivation and meiosis resumption were prevented in calphostin C-loaded eggs following treatment with A23187, even though the ionophore-induced Ca2+ signalling was not affected. Taken together, our results indicate that stimulation of PKC is a sufficient and necessary event to induce meiosis resumption in mouse eggs and strongly suggest that, in this species, the mechanism by which a transient calcium burst triggers MPF inactivation involves a PKC-dependent pathway. Mol. Reprod. Dev. 48:292–299, 1997. © 1997 Wiley-Liss, Inc. 相似文献
88.
In this study, we have examined several physiological, biochemical and morphological features of Buddleja davidii plants growing at 1300 m above sea level (a.s.l.) and 3400 m a.s.l., respectively, to identify coordinated changes in leaf properties in response to reduced CO2 partial pressure (Pa). Our results confirmed previous findings that foliar δ13C, photosynthetic capacity and foliar N concentration on a leaf area basis increased, whereas stomatal conductance (gs) decreased with elevation. The net CO2 assimilation rate (Amax), maximum rate of electron transport (Jmax) and respiration increased significantly with elevation, although no differences were found in carboxylation efficiency of Rubisco (Vcmax). Consequently, also the Jmax to Vcmax ratio was significantly increased by elevation, indicating that the functional balance between Ribulose‐1,5‐biphosphate (RuBP) consumption and RuBP regeneration changes as elevation increases. Our results also indicated a homeostatic response of CO2 transfer conductance inside the leaf (mesophyll conductance, gm) to increasing elevation. In fact, with elevation, gm also increased compensating for the strong decrease in gs and, thus, in the Pi (intercellular partial pressure of CO2) to Pa ratio, leading to similar chloroplast partial pressure of CO2 (Pc) to Pa ratio at different elevations. Because there were no differences in Vcmax, also A measured at similar PPFD and leaf temperature did not differ statistically with elevation. As a consequence, a clear relationship was found between A and gm, and between A and the sum of gs and gm. These data suggest that the higher dry mass δ13C of leaves at the higher elevation, indicative of lower long‐term Pc/Pa ratio, cannot be attributed to changes either in diffusional resistances or in carboxylation efficiency. We speculate that because temperature significantly decreases as the elevation increases, it dramatically affects CO2 diffusion and hence Pc/Pa and, consequently, is the primary factor influencing 13C discrimination at high elevation. 相似文献
89.
Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer 总被引:30,自引:0,他引:30
Viglietto G Motti ML Bruni P Melillo RM D'Alessio A Califano D Vinci F Chiappetta G Tsichlis P Bellacosa A Fusco A Santoro M 《Nature medicine》2002,8(10):1136-1144
The cyclin-dependent kinase inhibitor p27(kip1) is a putative tumor suppressor for human cancer. The mechanism underlying p27(kip1) deregulation in human cancer is, however, poorly understood. We demonstrate that the serine/threonine kinase Akt regulates cell proliferation in breast cancer cells by preventing p27(kip1)-mediated growth arrest. Threonine 157 (T157), which maps within the nuclear localization signal of p27(kip1), is a predicted Akt-phosphorylation site. Akt-induced T157 phosphorylation causes retention of p27(kip1) in the cytoplasm, precluding p27(kip1)-induced G1 arrest. Conversely, the p27(kip1)-T157A mutant accumulates in cell nuclei and Akt does not affect p27(kip1)-T157A-mediated cell cycle arrest. Lastly, T157-phosphorylated p27(kip1) accumulates in the cytoplasm of primary human breast cancer cells coincident with Akt activation. Thus, cytoplasmic relocalization of p27(kip1), secondary to Akt-mediated phosphorylation, is a novel mechanism whereby the growth inhibitory properties of p27(kip1) are functionally inactivated and the proliferation of breast cancer cells is sustained. 相似文献
90.
Giuseppe Sorrentino Matthew Haworth Said Wahbi Tariq Mahmood Shi Zuomin Mauro Centritto 《PloS one》2016,11(2)
The rate of photosynthesis (A) of plants exposed to water deficit is a function of stomatal (gs) and mesophyll (gm) conductance determining the availability of CO2 at the site of carboxylation within the chloroplast. Mesophyll conductance often represents the greatest impediment to photosynthetic uptake of CO2, and a crucial determinant of the photosynthetic effects of drought. Abscisic acid (ABA) plays a fundamental role in signalling and co-ordination of plant responses to drought; however, the effect of ABA on gm is not well-defined. Rose, cherry, olive and poplar were exposed to exogenous ABA and their leaf gas exchange parameters recorded over a four hour period. Application with ABA induced reductions in values of A, gs and gm in all four species. Reduced gm occurred within one hour of ABA treatment in three of the four analysed species; indicating that the effect of ABA on gm occurs on a shorter timescale than previously considered. These declines in gm values associated with ABA were not the result of physical changes in leaf properties due to altered turgor affecting movement of CO2, or caused by a reduction in the sub-stomatal concentration of CO2 (Ci). Increased [ABA] likely induces biochemical changes in the properties of the interface between the sub-stomatal air-space and mesophyll layer through the actions of cooporins to regulate the transport of CO2. The results of this study provide further evidence that gm is highly responsive to fluctuations in the external environment, and stress signals such as ABA induce co-ordinated modifications of both gs and gm in the regulation of photosynthesis. 相似文献