Data di Pubblicazione:
2013
Citazione:
Sphingomyelin synthase 1 activity is regulated by the BCR-ABL oncogene / T. Burns, M. Subathra, P. Signorelli, Y. Choi, X. Yang, Y. Wang, M. Villani, K. Bhalla, D. Zhou, C. Luberto. - In: JOURNAL OF LIPID RESEARCH. - ISSN 0022-2275. - 54:3(2013 Mar), pp. 794-805.
Abstract:
Sphingomyelin synthase (SMS) produces sphingomyelin (SM) while consuming
ceramide (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, hallmark of CML, as 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 siRNAmediated
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
sphingomyelin synthase; diacylglycerol; Bcr-abl
Elenco autori:
T. Burns, M. Subathra, P. Signorelli, Y. Choi, X. Yang, Y. Wang, M. Villani, K. Bhalla, D. Zhou, C. Luberto
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