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MessagePosté le: Mer 13 Aoû - 09:26 (2014) Sujet du message: However, despite the presence of the MAPK inhibitors, the c Répondre en citant

 Subsequently, PLC and Huh7 cells were treated with transcription inhibitor actinomycin D in the presence or absence of ABT 263. As shown in Figure 3C, ABT 263 co treatment significantly enhanced the mRNA stability of INNO-406 構造 Mcl 1 compared to Act D treat ment alone. These results indicated that ABT 263 upregulated Mcl 1 mRNA level via increasing the mRNA stability instead of activating its transcription in HCC cells. ABT 263 increases the protein stability of Mcl 1 To assess whether the increase of Mcl 1 protein solely results from the upregulation of Mcl 1 mRNA, the HCC cells were treated with translation inhibitor cyclohexi mide. As shown in Figure 4A and B, the level of Mcl 1 protein decreased dramatically after treatment with CHX alone, and the half life of Mcl 1 protein was 30 min.

Co treatment with ABT 263 and CHX mark edly attenuated the degradation of Mcl 1 protein, and the half life of Mcl 1 protein reached to more than 4 h. These results indicated that ABT 263 enhanced Mcl 1 protein stabilization in HCC cells. Meanwhile, ABT 263 could not further upregulate Lapatinib 溶解度 Mcl 1 protein level after proteasome was inhibited by MG132, suggesting that ABT 263 might upregulate Mcl 1 protein level by de creasing proteasome mediated degradation. As to whether ABT 263 affected the ubiquitination mediated Mcl 1 degradation, the role of deubiquitinase USP9X was in vestigated. As shown in Figure 4D and E, knockdown of USP9X didnt affect ABT 263 mediated Mcl 1 accumu lation, indicating that USP9X mediated deubiquitina tion doesnt contribute to ABT 263 enhanced Mcl 1 stability.

Activation LY2109761 TGF-beta/Smad 阻害剤 of ERK and JNK involves in ABT 263 induced stabilization of Mcl 1 protein It is known that there is a unique PEST region in Mcl 1 protein and the phosphorylation of this region is closely associated with Mcl 1 protein stability, so we ana lyzed the activity of several kinases which directly phos phorylate Mcl 1, including extracellular regulated kinase and c Jun terminal kinase. Meanwhile, phos phorylation of mammalian target of rapamycin was also detected upon ABT 263 treatment since its acti vation through phosphorylation can regulate the trans lational process of Mcl 1 protein. As shown in Figure 5A, ERK and JNK were activated while mTOR was repressed after treatment with ABT 263. To further clarify the role of these kinases in ABT 263 enhanced Mcl 1 pro tein stabilization, their inhibitors were used.

ERK inhibitor U0126 and JNK inhibitor SP600125, but not mTOR in hibitor rapamycin, markedly attenuated ABT 263 caused Mcl 1 upregulation. Moreover, ERK and JNK inhibitors significantly increased ABT 263 induced apop tosis in PLC and Huh7 cells revealed by annexin V FITC PI staining flow cytometry analysis, trypan blue exclusion assay and Western blot for en hanced PARP cleavage. These results indicated that activation of ERK and JNK, but not mTOR, involved in ABT 263 mediated Mcl 1 protein stabilization and drug resistance. ABT 263 enhances ERK and JNK mediated Mcl 1Thr163 phosphorylation To further investigate the concrete mechanisms of ERK and JNK mediated Mcl 1 stabilization, the phosphoryl ation status of Mcl 1Thr163 was analyzed.

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MessagePosté le: Mer 13 Aoû - 09:26 (2014) Sujet du message: Publicité

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