ÿþOver-expression of EGFR and EGFRvIII is a major hallmark puma sneakers dames of GBM. Although, both receptors have been linked to GBM resistance to chemotherapy, the mechanisms underlying this association are still unclear. Our findings in this study provide evidence that both EGFR and EGFRvIII negatively regulate intrinsic mitochondria-mediated apoptosis by binding to PUMA, a proapoptotic protein that is highly expressed in the majority of GBM. Following the interactions of EGFR/EGFRvIII with PUMA, PUMA is sequestered in the cytoplasm, leading to impaired apoptotic response in GBM. Our results also demonstrate that EGFR/EGFRvIII-mediated antagonism of PUMA is independent of EGFR/EGFRvIII kinase activity and thus, may define a novel mechanism of tumor resistance to apoptosis-inducing EGFR inhibitors.
Our data also provide a rationale for a novel GBM therapy, in which both the kinase-dependent and -independent activities of EGFR/EGFRvIII are targeted simultaneously in order to improve EGFR-based mono and combinational therapies.The results in this study showing GBMs, known to be highly resistant to therapy, to express high levels of the proapoptotic protein, PUMA, is paradoxical. To gain insight into this paradox, we investigated EGFR and EGFRvIII, frequently over-expressed in GBM similar to PUMA, and found both pathways to be inversely linked to the puma rs0 apoptotic response of GBM cells. These results allow the speculation that a subset of GBMs (34%) is capable of up-regulating EGFR/EGFRvIII expression in order to negatively regulate PUMA and thereby, escape therapy-induced apoptosis. Our results, however, also indicate that PUMA can be negatively regulated by EGFR/EGFRvIII-independent mechanisms, given the fact ( Fig. 2a ) that a portion of PUMA-expressing GBMs do not express EGFR/EGFRvIII.
Future puma rs-0 investigation is thus needed to identify these mechanisms in order to augment the apoptotic effects of anti-GBM therapy.The functional interaction between EGFR/EGFRvIII and PUMA potentially represents a new class of protein-protein interaction that involves a receptor tyrosine kinase and a proapoptotic protein. It is well known that EGFR can engage in protein-protein interactions with a variety of proteins, including, transcription factors, STAT3 [ 43 ], STAT5 [ 44 ] and E2F1 [ 45 ], DNA-dependent protein kinase [ 46 ], and the DNA replication and damage repair protein PCNA [ 47 ]. EGFR-STAT3 interactions lead to transcriptional activation of several cancer-related genes, including, inducible nitric oxide synthase [ 34 ], TWIST [ 48 ] and COX-2 [ 49 ].
Our results showed that Iressa, an EGFR-targeted tyrosine kinase inhibitor, fails to puma werkschoenen disrupt the interaction between EGFR/EGFRvIII and PUMA, suggesting that this kinase-independent anti-apoptotic activity may be an important mechanism underlying the limited clinical efficacy demonstrated by EGFR-targeted therapy. These observations also suggest that a higher therapeutic efficacy may be achieved by targeting both kinase-dependent and -independent functions of EGFR. In support of this premise, our data showed that mimicking PUMA's proapoptotic activity using a Bcl-2/Bcl-xL inhibitor sensitized both EGFR- and EGFRvIII-expressing GBM cells to Iressa and that most GBM cell lines we analyzed expressed high levels of Bcl-2 and Bcl-xL. Collectively, these findings provide strong evidence for a novel mechanism by which EGFR confers GBM resistance to EGFR-targeted therapy and potentially other therapies, as well as, provide a rationale for a novel combinational anti-GBM therapy that target both EGFR and intrinsic apoptotic pathways.
Camera trapping has advantages over radiotelemetry in its potential to provide data on the complete array of individuals within the study area. The 23 individually identified male jaguars showed high levels of overlap in ranges, with up to 5 different males captured at the same location in the same month. Low levels of avoidance between individuals and a high flux of individuals contributed to low consistency in home-range ownership over the long term (3 months to 2 years). Jaguars and pumas had similar nocturnal activity schedules. Both species used similar habitats within the Cockscomb Basin, indicated by a high correlation in capture rates per location between species. Apart from their overall spatial similarities, jaguars and pumas avoided using the same location at the same time. This interspecific segregation was detectable over and above the spatial and temporal segregation of individual jaguars.
Usamos muestreos intensivos de cámaras-trampa para estudiar las interacciones inter-individuales entre individuos identificados de jaguar ( Panthera onca ) y puma rs puma ( Puma concolor ). Datos de ubicaciones temporales de una red de 119 estaciones de trampeo en la cuenca del Cockscomb en Belice proporcionó la primera evidencia de que ambas especies se evitan espacialmente, datos que fueron calibrados con la información de las interacciones intraespecíficas de los jaguares. El uso de cámaras-trampa tiene ventajas sobre a radio-telemetría para proveer de datos de un conjunto de individuos de una área de estudio.Los 23 jaguares identificados individualmente mostraron un alto grado de sobreposición de sus áreas de actividad, con hasta 5 individuos fotografiados en el mismo sitio en un mes.
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