Fig. 1

Isotretinoin-induced p53-mediated sebocyte apoptosis. In the sebocyte, isotretinoin is isomerized to all-trans-retinoic acid (ATRA), which is transported to the nucleus via cellular retinoic acid binding protein 2 (CRABP2). In the nucleus, ATRA binds to retinoic acid receptor (RAR) and activates RAR-responsive genes such as TP53, which promotes the expression of p53. ATRA-induced expression of ARF promotes the expression of p14, which is a negative regulator of mouse double minute 2 (MDM2), the key inhibitor of p53 via proteasomal degradation of p53. Increased IGF-1 signalling is attenuated by p53 and reduces the activity of the kinase AKT, that via phosphorylation inhibits the activity of FoxO1 and FoxO3 but stimulates MDM2. Thus, isotretinoin increases p53 activity via its direct transcriptional induction and posttranslational inhibition of its negative regulator MDM2. Subsequently, increased p53 activates several apoptosis-promoting proteins such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). p53-attenuated IGF-1 signalling reduces the expression of survivin, a critical inhibitor of caspase 3. p53-induced expression of BLIMP1 and FoxO3 suppresses c-Myc, a key transcription factor of sebocyte differentiation. The final outcome is sebocyte apoptosis, the primary mechanism of isotretinoin-induced sebum suppression