All-trans retinoic acid (ATRA) has been successfully used in differentiation therapy for acute promyelocytic leukemia (APL) in clinic.ATRA-induced differentiation of leukemia cells is accompanied with G0/G1 arrest.yet how ATRA couples cell cycle arrest to differentiation remains largely unknown.Here we observed that ubiquitin-proteasome pathway (UPP) was activated upon ATRAtreatment in human acute myeloid leukemia NB4 and HL-60 cells.represented by the accumulation of ubiquitinated general proteins.the up-regulatedmRNA level of ubiquitin and the increased 20S proteasome activity.Interestingly.we found that complete inhibition of the proteasome activity suppressed ATRA-induced proliferation/differentiation (P/D) transition in both cell lines.Furthermore.we demonstrated that the exact protein contributing to this phenomenon was different in these two cell lines.namely,cyclin-dependent kinase 2 (CDK2) and Cyclin E were respectively degraded by the UPP and significantly accumulated after complete inhibition of proteasome in ATRA-treated NB4 and HL-60 cells.These findings suggested that the UPP might be indispensable in ATRA-induced G0/G1 arrest and differentiation of leukemia cells.however.the exact protein degraded by the UPP to promote the myeloid maturation program set in motion by the retinoid might be different and cell type specific.