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c-Cbl Interacts with CD38 and Promotes Retinoic Acid–Induced Differentiation and G₀ Arrest of Human Myeloblastic Leukemia Cells

Department of Biomedical Sciences, Cornell University, Ithaca, New York

Requests for reprints: Andrew Yen, Department of Biomedical Sciences, Cornell University, T4-008, VRT, Ithaca, NY 14853. Phone: 607-253-3354; Fax: 607-253-3317; E-mail: ay13{at}cornell.edu.

Key Words: Interaction • c-Cbl • CD38 • differentiation • cell cycle arrest

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 G₀ 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 G₀-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. [Cancer Res 2008;68(21):8761–9]

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