In:
Genes to Cells, Wiley, Vol. 23, No. 1 ( 2018-01), p. 22-34
Abstract:
Chronic myeloid leukemia ( CML ) is caused by the chimeric protein p210 BCR ‐ ABL encoded by a gene on the Philadelphia chromosome. Although the kinase domain of p210 BCR ‐ ABL is an active driver of CML , the pathological role of its pleckstrin homology ( PH ) domain remains unclear. Here, we carried out phospholipid vesicle‐binding assays to show that cardiolipin ( CL ), a characteristic mitochondrial phospholipid, is a unique ligand of the PH domain. Arg726, a basic amino acid in the ligand‐binding region, was crucial for ligand recognition. A subset of wild‐type p210 BCR ‐ ABL that was transiently expressed in HEK 293 cells was dramatically translocated from the cytosol to mitochondria in response to carbonyl cyanide m ‐chlorophenylhydrazone ( CCCP ) treatment, which induces mitochondrial depolarization and subsequent externalization of CL to the organelle's outer membrane, whereas an R726A mutant of the protein was not translocated. Furthermore, only wild‐type p210 BCR ‐ ABL , but not the R726A mutant, suppressed CCCP ‐induced mitophagy and subsequently enhanced reactive oxygen species production. Thus, p210 BCR ‐ ABL can change its intracellular localization via interactions between the PH domain and CL to cope with mitochondrial damage. This suggests that p210 BCR ‐ ABL could have beneficial effects for cancer proliferation, providing new insight into the PH domain's contribution to CML pathogenesis.
Type of Medium:
Online Resource
ISSN:
1356-9597
,
1365-2443
DOI:
10.1111/gtc.2018.23.issue-1
Language:
English
Publisher:
Wiley
Publication Date:
2018
detail.hit.zdb_id:
2020308-1
SSG:
12
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