dc.contributor.author | Ghazaly, EA | |
dc.contributor.author | Miraki-Moud, F | |
dc.contributor.author | Smith, P | |
dc.contributor.author | Gnanaranjan, C | |
dc.contributor.author | Koniali, L | |
dc.contributor.author | Oke, A | |
dc.contributor.author | Saied, MH | |
dc.contributor.author | Petty, R | |
dc.contributor.author | Matthews, J | |
dc.contributor.author | Stronge, R | |
dc.contributor.author | Joel, SP | |
dc.contributor.author | Young, BD | |
dc.contributor.author | Gribben, J | |
dc.contributor.author | Taussig, DC | |
dc.date.accessioned | 2020-10-08T14:36:17Z | |
dc.date.issued | 2020-04 | |
dc.identifier.citation | The Journal of biological chemistry, 2020, 295 (16), pp. 5496 - 5508 | |
dc.identifier.issn | 0021-9258 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4132 | |
dc.identifier.eissn | 1083-351X | |
dc.identifier.doi | 10.1074/jbc.ra119.010467 | |
dc.description.abstract | Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene ( SPHKAP ) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP -transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity. | |
dc.format | Print-Electronic | |
dc.format.extent | 5496 - 5508 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | K562 Cells | |
dc.subject | Tumor Cells, Cultured | |
dc.subject | Humans | |
dc.subject | Phosphotransferases (Alcohol Group Acceptor) | |
dc.subject | Ceramides | |
dc.subject | Adaptor Proteins, Signal Transducing | |
dc.subject | Leukemia, Myeloid, Acute | |
dc.title | Repression of sphingosine kinase (SK)-interacting protein (SKIP) in acute myeloid leukemia diminishes SK activity and its re-expression restores SK function. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1074/jbc.ra119.010467 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-04 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | The Journal of biological chemistry | |
pubs.issue | 16 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Acute Leukaemia | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Acute Leukaemia/Acute Leukaemia (hon.) | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Acute Leukaemia | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Acute Leukaemia/Acute Leukaemia (hon.) | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.publication-status | Published | |
pubs.volume | 295 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Acute Leukaemia | en_US |
dc.contributor.icrauthor | Taussig, David | |
dc.contributor.icrauthor | Stronge, Randal | |