title: Sphingomyelin synthase 1 activity is regulated by the BCR-ABL oncogene.
abstract: Sphingomyelin synthase (SMS) produces sphingomyelin while consuming ceramide (a negative regulator of cell proliferation) and forming diacylglycerol (DAG) (a mitogenic factor). Therefore, enhanced SMS activity could favor cell proliferation. To examine if dysregulated SMS contributes to leukemogenesis, we measured SMS activity in several leukemic cell lines and found that it is highly elevated in K562 chronic myelogenous leukemia (CML) cells. The increased SMS in K562 cells was caused by the presence of Bcr-abl, a hallmark of CML; stable expression of Bcr-abl elevated SMS activity in HL-60 cells while inhibition of the tyrosine kinase activity of Bcr-abl with Imatinib mesylate decreased SMS activity in K562 cells. The increased SMS activity was the result of up-regulation of the Sms1 isoform. Inhibition of SMS activity with D609 (a pharmacological SMS inhibitor) or down-regulation of SMS1 expression by siRNA selectively inhibited the proliferation of Bcr-abl-positive cells. The inhibition was associated with an increased production of ceramide and a decreased production of DAG, conditions that antagonize cell proliferation. A similar change in lipid profile was also observed upon pharmacological inhibition of Bcr-abl (K526 cells) and siRNA-mediated down-regulation of BCR-ABL (HL-60/Bcr-abl cells). These findings indicate that Sms1 is a downstream target of Bcr-abl, involved in sustaining cell proliferation of Bcr-abl-positive cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC.
authors.forename: Tara Ann
authors.initials: TA
authors.lastname: Burns
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC.
authors.forename: Marimuthu
authors.initials: M
authors.lastname: Subathra
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, San Paolo University Hospital, Medical School, University of Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Signorelli
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC.
authors.forename: Young
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yang
authors.affiliation: Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC; Pathology and Laboratory Medicine, Polispecialistica Bios, Crotone, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Villani
authors.affiliation: Pathology and Laboratory Medicine, The University of Kansas Cancer Center, Kansas City, KS.
authors.forename: Kapil
authors.initials: K
authors.lastname: Bhalla
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR.
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC.
authors.forename: Chiara
authors.initials: C
authors.lastname: Luberto
mesh_terms: D001549:Benzamides; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002460:Cell Line; D002518:Ceramides / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D016313:Genes, abl / Q000235:genetics / Q000502:physiology*; D018922:HL-60 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009636:Norbornanes; D010879:Piperazines; D011743:Pyrimidines; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D001952:Bridged-Ring Compounds; D002518:Ceramides; D004075:Diglycerides; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009636:Norbornanes; D010879:Piperazines; D011743:Pyrimidines; D013859:Thiocarbamates; D013871:Thiones; C046498:tricyclodecane-9-yl-xanthogenate; D000068877:Imatinib Mesylate; C455440:SGMS1 protein, human; D017855:Transferases (Other Substituted Phosphate Groups)