MCPIP1 Exogenous Overexpression Inhibits Pathways Regulating MYCN Oncoprotein Stability in Neuroblastoma

• Published in: Journal of cellular biochemistry 2017-07, Vol.118 (7), p.1741-1755
• Main Authors: Boratyn, Elżbieta, Nowak, Iwona, Durbas, Małgorzata, Horwacik, Irena, Sawicka, Anna, Rokita, Hanna
• Format: Article
• Language: English
• Subjects: AKT protein; AKT/mTOR PATHWAY; Apoptosis; Apoptosis - genetics; Apoptosis - physiology; Aurora Kinase A - genetics; Aurora Kinase A - metabolism; Biotechnology; Blotting, Western; Cancer; Cdc2 protein; CDC2 Protein Kinase - genetics; CDC2 Protein Kinase - metabolism; Cell Differentiation - genetics; Cell Differentiation - physiology; Cell Line, Tumor; Destabilization; Differentiation; Gene expression; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; Humans; MCPIP1; mRNA; mRNA stability; MYCN; N-Myc Proto-Oncogene Protein - genetics; N-Myc Proto-Oncogene Protein - metabolism; NEUROBLASTOMA; Neuroblastoma - genetics; Neuroblastoma - metabolism; Oncoproteins; Phosphorylation; Phosphorylation - genetics; Phosphorylation - physiology; Protein Stability; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Ribonucleases - genetics; Ribonucleases - metabolism; RNase; Signal transduction; Signal Transduction - genetics; Signal Transduction - physiology; Stability; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.25832

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. We show that exogenous expression of the MCPIP1 protein affects levels or phosphorylation of MYCN oncoprotein and its partners such as Aurora A (Thr288), CDC2 (Tyr15 and Thr161), GSK3β (Ser9), and other key cellular components of Akt/mTOR signaling, which regulate MYCN stability and activation. Moreover, exogenous expression of MCPIP1 does not cause apoptosis. Our data extend knowledge on roles of MCPIP1 in neuroblastoma cells and link the protein to regulation of expression and stability of MYCN through decrease of signaling via Akt/mTOR pathway.