Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10901924 | Cancer Letters | 2015 | 7 Pages |
Abstract
SH3 domain plays an important role in maintaining autoinhibition of BCR-ABL protein. RIN1 interacts with BCR-ABL SH3 domain via PxxP motifs to promote autophosphorylation as well as activation of BCR-ABL tyrosine kinase, suggesting using exogenous SH3 domain which blocks the interaction of BCR-ABL and RIN1 could be an adjunct therapy for CML. Here, we reported a novel p-BCR-ABL inhibitor, designed as ABL SH3 mutant, and identified its effects on inhibiting the tyrosine kinase activity of BCR-ABL without or with imatinib (IM) in vitro and in vivo. Our results demonstrated that ABL SH3 mutant T79Y markedly repressed the expression of BCR-ABL signaling pathways in IM-resistant cell lines KCL22 and K562/G01 as well as IM-sensitive cell line K562. Moreover, combination of T79Y with IM considerably decreased the proliferation of leukemia cells in vivo. Inhibition of BCR-ABL and RIN1 interaction using exogenous modified BCR-ABL SH3 domain provides a feasible and alternative option of small molecule inhibitors for CML treatment.
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Authors
Xin Liu, Yajuan Li, Liangxue Wen, Kun Tao, Qing Xiao, Weixi Cao, Zhenglan Huang, Miao Gao, Hui Li, Fang Wang, Wenli Feng,