title: Gene expression profiling reveals the role of RIG1 like receptor signaling in p53 dependent apoptosis induced by PUVA in keratinocytes.
abstract: Photochemotherapy using 8-methoxypsoralen in combination with UVA radiation (PUVA) is an effective treatment for various skin dermatosis including psoriasis however its molecular mechanism is not clear. Previously we demonstrated that PUVA differentially regulates miRNA expression profile with a significant up-regulation of hsa-miR-4516. To study in detail the molecular mechanism of PUVA in keratinocytes, we investigated the genome wide transcriptomic changes using Illumina whole genome gene expression beadchip. Microarray analysis revealed 1932 differentially expressed gene and their Insilico analysis revealed Retinoic Acid Inducible Gene-I (RIG-1) signaling, apoptosis and p53 pathway to be associated with PUVA induced effects. We demonstrate that miR-4516 mediated down-regulation of UBE2N promotes p53 nuclear translocation and pro-apoptotic activity of PUVA is independent of IRF3 but is mediated by the RIG-I in a p53 and NFκB dependent manner. Additionally, PUVA inactivated the AKT/mTOR pathway in concert with inhibition of autophagy and suppressed cell migration. Taken together this study broadens our understanding about the mechanism of action of PUVA providing possible new strategy targeting proapoptotic function of RIG-1, a regulator of innate immune response or p53 for psoriasis therapy.
authors.affiliation: Functional Genomics Unit, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi -110007, India.
authors.forename: Shruti
authors.initials: S
authors.lastname: Chowdhari
authors.affiliation: Functional Genomics Unit, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi -110007, India. Electronic address: nsaini@igib.in.
authors.forename: Neeru
authors.initials: N
authors.lastname: Saini
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008730:Methoxsalen / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics; D011701:PUVA Therapy / Q000379:methods; D011971:Receptors, Immunologic; D012867:Skin / Q000187:drug effects; D012878:Skin Neoplasms / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C000591812:MIRN-4516 microRNA, human; D035683:MicroRNAs; D011971:Receptors, Immunologic; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D008730:Methoxsalen
keywords: Apoptosis; PUVA; Psoriasis; RIG-1 like receptor signaling; miR-4516/UBE2N axis; p53