title: MCPIP1 contributes to clear cell renal cell carcinomas development.
abstract: Monocyte Chemoattractant protein-induced protein 1 (MCPIP1), also known as Regnase-1, is encoded by the ZC3H12a gene, and it mediates inflammatory processes by regulating the stability of transcripts coding for proinflammatory cytokines and controlling activity of transcription factors, such as NF-κB and AP1. We found that MCPIP1 transcript and protein levels are strongly downregulated in clear cell renal cell carcinoma (ccRCC) samples, which were derived from patients surgically treated for renal cancer compared to surrounded normal tissues. Using Caki-1 cells as a model, we analyzed the role of MCPIP1 in cancer development. We showed that MCPIP1 expression depends on the proteasome activity; however, hypoxia and hypoxia inducible factor 2 alfa (HIF2α) are key factors lowering MCPIP1 expression. Furthermore, we found that MCPIP1 negatively regulates HIF1α and HIF2α levels and in the case of the last one, the mechanism is based on the regulation of the half time of transcript coding for HIF2α. Enhanced expression of MCPIP1 in Caki-1 cells results in a downregulation of transcripts encoding VEGFA, GLUT1, and IL-6. Furthermore, MCPIP1 decreases the activity of mTOR and protein kinase B (Akt) in normoxic conditions. Taken together, MCPIP1 contributes to the ccRCC development.
authors.affiliation: Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 7 Gronostajowa St, 30-387, Krakow, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Ligeza
authors.affiliation: Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 7 Gronostajowa St, 30-387, Krakow, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Marona
authors.affiliation: Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 7 Gronostajowa St, 30-387, Krakow, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gach
authors.affiliation: Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 7 Gronostajowa St, 30-387, Krakow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Lipert
authors.affiliation: Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 7 Gronostajowa St, 30-387, Krakow, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Miekus
authors.affiliation: Center of Oncology, Maria Skłodowska-Curie Memorial Institute, Garncarska 11, 31-115, Krakow, Poland.
authors.forename: Waclaw
authors.initials: W
authors.lastname: Wilk
authors.affiliation: Center of Oncology, Maria Skłodowska-Curie Memorial Institute, Garncarska 11, 31-115, Krakow, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Jaszczynski
authors.affiliation: Center of Oncology, Maria Skłodowska-Curie Memorial Institute, Garncarska 11, 31-115, Krakow, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Stelmach
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.|Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Loboda
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.|Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Jozef
authors.initials: J
authors.lastname: Dulak
authors.affiliation: Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 7 Gronostajowa St, 30-387, Krakow, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Branicki
authors.affiliation: Center of Oncology, Maria Skłodowska-Curie Memorial Institute, Garncarska 11, 31-115, Krakow, Poland. z5rys@cyf-kr.edu.pl.
authors.forename: Janusz
authors.initials: J
authors.lastname: Rys
authors.affiliation: Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 7 Gronostajowa St, 30-387, Krakow, Poland. jolanta.jura@uj.edu.pl.
authors.forename: Jolanta
authors.identifier: http://orcid.org/0000-0002-0816-3475
authors.initials: J
authors.lastname: Jura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology*; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012260:Ribonucleases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051272:Glucose Transporter Type 1; D007976:Leupeptins; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D012260:Ribonucleases; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C510646:ZC3H12A protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Angiogenesis; Clear cell renal cell carcinoma (ccRCC); HIF1α; HIF2α; MCPIP1 (Regnase-1)