ATRA up-regulates UBE2D3 (E2) in APL cells, leading to ubiquitination of cyclin D1 (steps 1–4, numbered in red; see text). Monoubiquitinated cyclin D1 is then polyubiquitinated and degraded in the proteasome (step 5). In the absence of UBE2D3, cyclin D1 is not degraded and cells continue to cycle.