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Up-regulation of the Cbl family of ubiquitin ligases is involved in ATRA and bufalin-induced cell adhesion but not cell differentiation.

Qu X, Liu Y, Ma Y, Zhang Y, Li Y, Hou K

Department of Medical Oncology, The First Hospital, China Medical University, NO. 155, North Nanjing Street, Heping District, Shenyang City, Liaoning 110001, China.

The Casitas B-lineage Lymphoma (Cbl) family of ubiquitin ligases is multifunctional proteins that play important roles in different cell signaling pathways. It has been reported that c-Cbl and Cbl-b mRNAs are up-regulated during TPA-induced U937 and HL-60 cell differentiation. But the mechanism of the up-regulation and the roles of the Cbl family of ubiquitin ligases still remain unclear. In the present study, we demonstrated that bufalin enhanced all-trans retinoic acid (ATRA) induced differentiation of HL-60 cells, accompanied by up-regulation of the Cbl family of ubiquitin ligases. CsA, an inhibitor of calcium mobilization, reversed this up-regulation. Pretreatment with CsA and PS-341 did not affect the expression of CD11b, but suppressed the percentage of adherent cells. Lipid raft localization of Cbl-b enhanced cell adhesion, while C-terminal deletion partially suppressed the effect. Moreover, the expression of the adhesion-related kinases Pyk2 and Paxillin was up-regulated in parallel with the increase of Cbl proteins. These results suggested that up-regulation of c-Cbl and Cbl-b was involved in the regulation of ATRA and bufalin-induced HL-60 cell adhesion rather than cell differentiation, which might be mediated by lipid raft localization, ubiquitin ligase activity and C-terminal structure of Cbl proteins. Meanwhile, up-regulation of proline-rich tyrosine kinase (Pyk2) and Paxillin might also be implicated in this regulation.

Published 18 January 2008 in Biochem Biophys Res Commun, 367(1): 183-9.
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