about the effects of dasatinib on lymphoma development in vitro. They compared dasatinib to Imatinib to help the notion that SFK but not other tyrosine kinases are essential for lymphoma development. Even so, proteomic approaches have demonstrated that dasatinib can impact other PTKs like BTK, Csk, as effectively as other Ser/Thr kinases like p38 MAPK. As a result, our study used siRNA to specifically knock down Lyn and thus demonstrated Lyn is required for lymphoma growth.
Furthermore, we have been able to show dasatinib efficacy in an in vivo lymphoma model. The evident query is: Why is Lyn kinase constitutively active in B lymphoma cells One chance is that Lyn is mutated in B lymphoma cells, which may be unlikely, given that Lyn is energetic in a amount of murine and human lymphoma cells. An additional possibility is that Lyn is constitutively active NSCLC due to the association of Lyn with lipid rafts that dont contain the negative regulator Csk in B lymphoma cells. In regular B cells, Lyn is only transiently activated in response to BCR engagement by antigen. Singh et al showed that BCR engagement led to a Ca2 dependent, speedy production of reactive oxygen species, in specific H2O2.
The ROS in turn led to a rapid and transient inhibition of protein tyrosine phosphatase activity linked with the BCR due to the oxidation of the important cysteine in the energetic web site of PTP and a transient increase in Lyn kinase activity. As a result the extent of PTP oxidation determines the activation status of Lyn. In the light of small molecule library this observation, and the information indicating a strong correlation between ROS and lymphomagenesis, it is conceivable that B lymphoma cells have a higher level of production of ROS than the standard B cells and the substantial degree of ROS immediately inactivates the PTPs, which brings about phosphorylation and constitutive activation of Lyn. In help of this, we observed a higher level of world-wide tyrosine phosphorylation in B lymphoma cells compared to the typical B cells.
It is intriguing to note that phosphorylation on Tyr507 of Lyn did not keep Lyn inactive and Lyn is still phosphorylated on Tyr396. It could be that above expression of Lyn kinase promotes their aggregation and leads to autophosphorylation on Tyr396 1st and an inactivation cyclic peptide synthesis of SHP 1 by ROS keeps this phosphorylation steady. After Lyn is phosphorylated on Tyr396, it might be much less impacted by the phosphorylation on Tyr507 due to an inactivation of CD45. The complexity of the function of Lyn in B cells versus B lymphomas is reminiscent of its damaging role in normal myeloid cell development and its beneficial role for the growth of chronic myeloid leukemia cells, in which Lyn inhibitors are previously becoming examined in clinic. Similarly acute myeloid leukemia cells express constitutively active Lyn and their growth is inhibited by PP2.
All round, our research recommend a model in which constitutive Lyn kinase activity phosphorylates Igand Igto mediate the constitutive BCR signaling for B lymphoma survival and development. Our data also recommend that like other sorts of cancers, B lymphomas are heterogeneous. In addition to possessing Factor Xa the constitutively energetic Lyn activity and constitutive BCR signaling, some lymphomas may have over expression of Bcl 2 anti apoptotic proteins due to chromosomal translocation of BCL2 gene into the Ig loci.
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