title: MCPIP1 Exogenous Overexpression Inhibits Pathways Regulating MYCN Oncoprotein Stability in Neuroblastoma.
abstract: The main physiological function of MCPIP1 (regnase-1) is negative regulation of inflammation. Moreover, roles of regnase-1 in apoptosis and differentiation have also been described, but its involvement in cancer is yet to be fully recognized. Earlier, we showed a lack of expression of MCPIP1 in both primary tumors and several neuroblastoma cell lines. Additionally, we reported that levels of MCPIP1 and the key neuroblastoma oncoprotein-MYCN were inversely correlated in BE(2)-C clones overexpressing the MCPIP1 gene. Here, we show that exogenous expression of the MCPIP1 protein decreases MYCN mRNA and protein levels without changing the MYCN mRNA half-life. Furthermore, it was shown that MCPIP1-wt exogenous expression affects levels and phosphorylation of MYCN partners such as Aurora A (Thr288), CDC2 (Tyr15 and Thr161), GSK3β (Ser9), and key cellular components of Akt/mTOR signaling, which regulate MYCN stability and activation. In accordance with the obtained results, we found increased phosphorylation of MYCN protein at Thr58 that causes destabilization of the oncoprotein. Moreover, it is shown that exogenous expression of MCPIP1 does not cause apoptosis. Our data extend knowledge on roles of MCPIP1 in our model and link the protein to regulation of expression and stability of MYCN through decrease of signaling via Akt/mTOR pathway. J. Cell. Biochem. 118: 1741-1755, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Laboratory of Molecular Genetics and Virology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Boratyn
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Laboratory of Molecular Genetics and Virology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland.
authors.forename: Iwona
authors.initials: I
authors.lastname: Nowak
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Laboratory of Molecular Genetics and Virology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Durbas
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Laboratory of Molecular Genetics and Virology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland.
authors.forename: Irena
authors.initials: I
authors.lastname: Horwacik
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Laboratory of Molecular Genetics and Virology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Sawicka
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Laboratory of Molecular Genetics and Virology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland.
authors.forename: Hanna
authors.identifier: 0000-0003-2675-2393
authors.initials: H
authors.lastname: Rokita
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012260:Ribonucleases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D014157:Transcription Factors; C546842:MTOR protein, human; D064096:Aurora Kinase A; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D012260:Ribonucleases; C510646:ZC3H12A protein, human
keywords: AKT/mTOR PATHWAY; MCPIP1; MYCN; NEUROBLASTOMA; RNase