title: Up-regulation of the Cbl family of ubiquitin ligases is involved in ATRA and bufalin-induced cell adhesion but not cell differentiation.
abstract: 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.
authors.affiliation: Department of Medical Oncology, The First Hospital, China Medical University, NO. 155, North Nanjing Street, Heping District, Shenyang City, Liaoning 110001, China.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Qu
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Liu
authors.forename: Yanju
authors.initials: Y
authors.lastname: Ma
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Li
authors.forename: Kezou
authors.initials: K
authors.lastname: Hou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002018:Bufanolides / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D018922:HL-60 Cells; D006801:Humans; D051419:Paxillin / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D002018:Bufanolides; D051419:Paxillin; D014212:Tretinoin; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C022777:bufalin