title: c-Cbl interacts with CD38 and promotes retinoic acid-induced differentiation and G0 arrest of human myeloblastic leukemia cells.
abstract: Retinoic acid (RA) is known to regulate cell growth and differentiation. In HL-60 human myeloblastic leukemia cells, it causes mitogen-activated protein kinase (MAPK) signaling leading to myeloid differentiation and G(0) cell cycle arrest. This communication reports that expression of the Cbl adaptor caused enhanced extracellular signal-regulated kinase 2 activation and promoted RA-induced differentiation and G(0)-arrest. Stable transfectants ectopically expressing c-Cbl underwent myeloid differentiation faster than wild-type (wt) cells when treated with RA. In contrast, c-Cbl knockdown stable transfectants differentiated slower than wt cells when treated with RA. Cells ectopically expressing c-Cbl had enhanced CD38 expression when treated with RA, and cells ectopically expressing CD38 had enhanced c-Cbl expression, even without with RA, suggesting an interaction between c-Cbl and CD38. Fluorescence resource energy transfer and coimmunoprecipitation showed that c-Cbl and CD38 bind each other. RA causes the gradual down-regulation and eventual loss of c-Cbl expression, resulting in loss of the Cbl-CD38 interaction, suggesting that c-Cbl plays a relatively early role in promoting RA-induced differentiation. RA-induced differentiation can thus be propelled by c-Cbl and by CD38, both of which bind together, enhance the expression of each other, and cause MAPK signaling. There thus seems to be a cooperative role for c-Cbl and CD38, reflected in their direct binding, in propulsion of RA-induced differentiation.
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Miaoqing
authors.initials: M
authors.lastname: Shen
authors.forename: Andrew
authors.initials: A
authors.lastname: Yen
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D017931:DNA Primers; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D018922:HL-60 Cells; D006801:Humans; D011485:Protein Binding; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D014212:Tretinoin; D050721:Proto-Oncogene Proteins c-cbl; D051997:ADP-ribosyl Cyclase 1; C067419:CBL protein, human