puma rs

ÿþOver-expression of EGFR and EGFRvIII is a major hallmark of GBM. puma sneakers dames 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 apoptotic response of GBM cells. puma rs0 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 investigation is thus needed to identify these puma rs-0 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 disrupt the interaction between EGFR/EGFRvIII and PUMA, suggesting that this puma werkschoenen 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.

Registramos baja consistencia en las áreas de actividad ("home ranges" en períodos de 3 meses a dos años, con bajos niveles de separación espacial entre individuos pero con un alto flujo de individuos. Los patrones de actividad nocturna de jaguares y pumas fueron similares. Ambas especies usaron hábitats similares en la cuenca del Cockscomb, indicado por una alta correlación en las tasas de captura por sitio entre las especies. A pesar de estos patrones, los jaguares y pumas evitaron usar el mismo sitio al mismo tiempo. Esta segregación interespecífica fue detectada sobre la segregación espacial y temporal de los individuos de jaguar.In the present study we employ this longer ND5 segment to investigate the evolutionary history of P. concolor , with emphasis on South American populations, which were previously found to harbor high levels of diversity and inferred to have played a key role in the historical demography of this species ( Culver et al. , 2000 ).

Given that the geographic sampling of South American pumas was limited in that first study, we aimed here to expand the representation of the puma rs various regions of this sub-continent, so as to allow refined inferences of population structure, maternal gene flow and demographic history. In addition to expanding the geographic coverage of South American regions to refine inferences on patterns of matrilineal subdivision, we have performed novel analyses on puma demographic history, which revealed consistent evidence of a recent population expansion in South America, prior to re-colonization of North America.We obtained blood and tissue samples from 77 pumas including wild individuals captured during field-ecology projects, caught by farmers or road-killed, as well as captive animals with known geographic origin ( Table S1 ).