As4S4 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 ubiquitination for many other receptor/protein tyrosine kinases. Our data showed that c-CBL protein was considerably up-regulated by arsenic sulfide (As(4)S(4)). 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.
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Jian-Hua
JH
Mao
Xiao-Yan
XY
Sun
Jian-Xiang
JX
Liu
Qun-Ye
QY
Zhang
Ping
P
Liu
Qiu-Hua
QH
Huang
Keqin Kathy
KK
Li
Quan
Q
Chen
Zhu
Z
Chen
Sai-Juan
SJ
Chen
D000595:Amino Acid Sequence; D000818:Animals; D001152:Arsenicals / Q000627:therapeutic use*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D011487:Protein Conformation; D050721:Proto-Oncogene Proteins c-cbl / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D013440:Sulfides / Q000627:therapeutic use*; D054875:Ubiquitination
D001152:Arsenicals; D046912:Multiprotein Complexes; D013440:Sulfides; C045816:arsenic trisulfide; D050721:Proto-Oncogene Proteins c-cbl; D016044:Fusion Proteins, bcr-abl