title: SGK1 affects RAN/RANBP1/RANGAP1 via SP1 to play a critical role in pre-miRNA nuclear export: a new route of epigenomic regulation.
abstract: The serum- and glucocorticoid-regulated kinase (SGK1) controls cell transformation and tumor progression. SGK1 affects mitotic stability by regulating the expression of RANBP1/RAN. Here, we demonstrate that SGK1 fluctuations indirectly modify the maturation of pre-miRNAs, by modulating the equilibrium of the RAN/RANBP1/RANGAP1 axis, the main regulator of nucleo-cytoplasmic transport. The levels of pre-miRNAs and mature miRNAs were assessed by qRT-PCR, in total extracts and after differential nuclear/cytoplasmic extraction. RANBP1 expression is the limiting step in the regulation of SGK1-SP1 dependent nuclear export. These results were validated in unrelated tumor models and primary human fibroblasts and corroborated in tumor-engrafted nude mice. The levels of pri-miRNAs, DROSHA, DICER and the compartmental distribution of XPO5 were documented. Experiments using RANGTP conformational antibodies confirmed that SGK1, through RANBP1, decreases the level of the GTP-bound state of RAN. This novel mechanism may play a role in the epigenomic regulation of cell physiology and fate.
authors.affiliation: University "Magna Graecia" of Catanzaro, Dept. of "Scienze della Salute", Viale Europa Catanzaro, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Dattilo
authors.affiliation: University "Magna Graecia" of Catanzaro, Dept. of "Scienze della Salute", Viale Europa Catanzaro, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: D'Antona
authors.affiliation: University "Magna Graecia" of Catanzaro, Dept. of "Scienze della Salute", Viale Europa Catanzaro, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Talarico
authors.affiliation: University "Magna Graecia" of Catanzaro, Dept. of "Scienze della Salute", Viale Europa Catanzaro, Italy.
authors.forename: Mjriam
authors.initials: M
authors.lastname: Capula
authors.affiliation: University "Magna Graecia" of Catanzaro, Dept. of "Scienze della Salute", Viale Europa Catanzaro, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Catalogna
authors.affiliation: University "Magna Graecia" of Catanzaro, Dept. of "Medicina Sperimentale e Clinica", Viale Europa Catanzaro, Italy.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Iuliano
authors.affiliation: University of Genova, Dept of Farmacia, Viale Benedetto XV 3, Genova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.affiliation: University "Federico II" of Naple, Dept of Medicina Veterinaria e Produzioni Animali, Via Federico Delpino 1, Napoli, Italy.
authors.forename: Sante
authors.initials: S
authors.lastname: Roperto
authors.affiliation: University "Magna Graecia" of Catanzaro, Dept. of "Medicina Sperimentale e Clinica", Viale Europa Catanzaro, Italy.
authors.forename: Cataldo
authors.initials: C
authors.lastname: Bianco
authors.affiliation: University "Magna Graecia" of Catanzaro, Dept. of "Scienze della Salute", Viale Europa Catanzaro, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Perrotti
authors.affiliation: University "Magna Graecia" of Catanzaro, Dept. of "Scienze della Salute", Viale Europa Catanzaro, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Amato
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D044127:Epigenesis, Genetic; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D020931:ran GTP-Binding Protein / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D017874:Immediate-Early Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D016329:Sp1 Transcription Factor; D020931:ran GTP-Binding Protein; D000099184:Serum-Glucocorticoid Regulated Kinases; C120587:RAN protein, human; C108209:SP1 protein, human; C091775:ran-binding protein 1