As^sub 4^S^sub 4^ targets RING-type E3 ligase c-CBL to induce degradation of BCR-ABL in chronic myelogenous leukemia

Arsenic, a curative agent for acute promyelocytic leukemia, induces cell apoptosis and degradation of BCR-ABL in chronic myelogenous leukemia (CML). We demonstrated that ubiquitination and degradation of BCR-ABL was mediated by c-CBL, a RING-type E3 ligase that was also shown to be involved in ubiqu...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2010-12, Vol.107 (50), p.21683
Main Authors: Mao, Jian-Hua, Sun, Xiao-Yan, Liu, Jian-Xiang, Zhang, Qun-Ye, Liu, Ping, Huang, Qiu-Hua, Li, Keqin Kathy, Chen, Quan, Chen, Zhu, Chen, Sai-Juan
Format: Article
Language:English
Subjects:
Apoptosis
Arsenic
Biochemistry
Enzymes
Kinases
Leukemia
Proteins
Rodents
Online Access:Get full text
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Summary:Arsenic, a curative agent for acute promyelocytic leukemia, induces cell apoptosis and degradation of BCR-ABL in chronic myelogenous leukemia (CML). We demonstrated that ubiquitination and degradation of BCR-ABL was mediated by c-CBL, a RING-type E3 ligase that was also shown to be involved in ubiquitination for many other receptor/protein tyrosine kinases. Our data showed that c-CBL protein was considerably up-regulated by arsenic sulfide (As...S...). Interestingly, arsenic directly bound the RING finger domain of c-CBL to inhibit its self-ubiquitination/degradation without interfering with the enhancement of ubiquitination and subsequent proteolysis of its substrate BCR-ABL. Degradation of BCR-ABL due to c-CBL induction as a result of arsenic treatment was also observed in vivo in CML mice. These findings provide insight into the molecular mechanisms of arsenic and further support its therapeutic applications in CML in combination with tyrosine kinase inhibitors and potentially also in other malignancies involving aberrant receptor/protein tyrosine kinase signaling. (ProQuest: ... denotes formulae/symbols omitted.)
ISSN:0027-8424
1091-6490