Fig. 2
Synoptic illustration of p53-activating anti-acne therapies. Systemic isotretinoin (13-cis retinoic acid) via isomerization to all-trans retinoic acid (ATRA), tretinoin (ATRA), as well as cytochrome p450-inhibiting tetracyclines and macrolides all enhance ATRA-mediated upregulation of p53. Benzoyl peroxide (BPO) and hydrogen peroxide (H2O2) enhance p53 expression as well as a azelaic acid (AZA)-induced mitochondrial damage and photodynamic therapy, which generate reactive oxygen species (ROS). Activated p53 attenuates the expression of IGF-1 receptor (IGF1R) and of androgen receptor (AR). p53 activates expression of cell cycle inhibitor p21 and via upregulation of IGF binding protein-3 (IGFBP3) suppresses the transactivation of peroxisome proliferator-activated receptor-γ (PPARγ), which is important for sebocyte differentiation. Oxidative stress-responsive sestrins activate AMP kinase (AMPK), which inhibits mechanistic target of rapamycin complex 1 (mTORC1) downregulating anabolism, cell growth and sterol regulatory element binding protein 1c (SREBP1c)- and PPARγ-dependent lipogenesis. p53-mediated upregulation of FoxO1 expression inhibits AR, PPARγ, and SREBP1c, key transcription factors of sebaceous lipogenesis and sebocyte differentiation. p53-induced expression of FoxO3a and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) activate pro-apoptotic signalling with upregulation of caspase 8 (Casp8) and caspase 3 (Casp3), which execute apoptosis and promote p63 degradation. p53 increases the expression of the ubiquitin E3 ligase MDM2, which inhibits nuclear factor κB (NFκB), the key transcription factor for inflammatory cytokine expression. Anti-androgens attenuate AR-mediated expression of miRNA-125b, a key negative regulator of p53. Thus, p53 upregulation balances all pathological deviations observed in the sebaceous follicle of patients with acne vulgaris: increased proliferation, exaggerated lipogenesis, and inflammation. Note, that p53 is suppressed in SV40 immortalized sebocytes, because SV40 large T antigen physically inhibits p53