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MessagePosté le: Mar 27 Mai - 07:13 (2014) Sujet du message: The challenge will be to estimate from the degree of synerg Répondre en citant

 Similarly, PP2 decreased BCR induced phospho Tyr397 LYN in pri mary MCL cells. Dasatinib also diminished BCR induced phospho JNK p46, positioning JNK as a downstream target of LYN in re sponse to BCR engagement. We following evaluated the im pact of dasatinib on basal and BCR induced level of EGR one ABT-888 PARP 阻害剤 like a target of JNK. As proven in Figure 5D, dasatinib decreased basal expression of EGR1 mRNA and fully abrogated its upregulation in response to BCR ligation. Dasatinib also somewhat decreased basal degree of EGR1 protein and blocked its BCR induced upregulation. Eventually, we evaluated the influence of PP2 and dasatinib therapy on BCR induced cell survival. Escalating concentrations of dasatinib abrogated the BCR induced survival response in a dose dependent manner and significantly suppressed this survival signal in all UPN cases examined.

Similarly, PP2 Afatinib 439081-18-2 therapy also diminished or abolished BCR induced cell survival. Total, these outcomes highlight the importance of LYN, JNK and EGR1 as intermediates of BCR signaling in mediating survival signals in MCL cells and point out on the effi ciency of dasatinib in suppressing cell survival signal em anating in the BCR. Discussion Inside the existing study, we showed that primary MCL cells displayed a constitutive and BCR induced activation of LYN and that therapy with dasatinib or which has a a lot more unique inhibitor of LYN suppressed both BCR induced JNK phosphorylation and EGR 1 upregulation and it is associated that has a lower of cell survival.

Latest studies have shown the importance of tonic BCR signaling in survival of DLBCL cells and CLL cells but number of research centered around the part of BCR sig naling in MCL cell survival. We have previously shown in MCL cells that BCR engagement induced a cell survival AG-1478 153436-53-4 signal as a result of an IL6 IL10 autocrine dependent activation of STAT3. To even further identify early genes involved in BCR induced survival, we looked with the dif ferential gene expression on BCR stimulation. We evidenced that BCR engagement led to a rapid but tran sient induction of mRNA and protein levels of EGR 1. EGR 1 is a zinc finger transcription element whose expres sion continues to be described as straight dependent on antigen receptor signaling. EGR 1 is a downstream target of JNK and it regulates the expression of numerous genes like CD44, NF kB1, thymidine kinase, cyclin D1 and platelet derived growth factor which can be important for cell survival and proliferation.

We so evaluated the position of EGR 1 in MCL cell survival and showed that inhibition of JNK by SP600125 induced a lessen of constitutive and BCR induced EGR one expression, associated with an increase of apoptosis as well as a suppres sion of BCR induced survival. We confirmed the JNK dependent upregulation of EGR one by blocking the activ ity of TAK1, the upstream activator of JNK, which was recently described to play an critical position in MCL sur vival. Our benefits indicate that in MCL cells, EGR one is a downstream target of BCR signaling and its expres sion is usually enhanced in response to antigen stimulation leading to cell survival.

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MessagePosté le: Mar 27 Mai - 07:13 (2014) Sujet du message: Publicité

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