The p73 gene is an anti-tumoral target of the RARbeta/gamma-selective retinoid tazarotene.
Tazarotene, a member of the new class of acetylenic retinoids, has been shown to be effective in the treatment of several hyperproliferative skin diseases, including non-melanoma skin cancer. Its effectiveness is thought to rely on the ability to activate retinoic acid receptors beta and gamma and to induce a number of downstream anti-proliferative genes. Here, we show that the p53-related gene p73 is a target of tazarotene. Indeed, tazarotene modulates the expression of the p73 gene in immortalized keratinocyte cell lines by inducing the pro-apoptotic and anti-proliferative TAp73 isoforms and by repressing the anti-apoptotic and pro-proliferative DeltaNp73 isoforms. This occurs at the transcriptional level through a coordinated action on P1p73 and P2p73 promoters that control the expression of TA and DeltaN isoforms, respectively. The selective downregulation of DeltaNp73 expression by small interfering RNA led to an enhancement of tazarotene-induced bax activation and apoptosis, whereas the downregulation of both TA and DeltaN isoforms impairs tazarotene-mediated apoptosis. These results indicate the relevance of p73 gene products in tazarotene-induced growth inhibition and effectiveness in the treatment of skin tumors.
Papoutsaki
Marina
M
Department of Dermatology, University of Rome Tor Vergata, Rome, Italy.
Lanza
Mauro
M
Marinari
Barbara
B
Nisticò
Steven
S
Moretti
Francesca
F
Levrero
Massimo
M
Chimenti
Sergio
S
Costanzo
Antonio
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D016147:Genes, Tumor Suppressor; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D007641:Keratolytic Agents / Q000494:pharmacology*; D051379:Mice; D009539:Nicotinic Acids / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins; D000097768:Retinoic Acid Receptor gamma; D012176:Retinoids
D004268:DNA-Binding Proteins; D007641:Keratolytic Agents; D009539:Nicotinic Acids; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000097768:Retinoic Acid Receptor gamma; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; C000606369:delta Np73 protein, human; C454920:delta Np73, mouse; C082925:retinoic acid receptor beta; C086827:tazarotene; D012176:Retinoids