Circadian Clock in a Mouse Colon Tumor Regulates Intracellular Iron Levels to Promote Tumor Progression.

Abstract

Iron is an important biological catalyst and is critical for DNA synthesis during cell proliferation. Cellular iron uptake is enhanced in tumor cells to support increased DNA synthesis. Circadian variations in DNA synthesis and proliferation have been identified in tumor cells, but their relationship with intracellular iron levels is unclear. In this study, we identified a 24-h rhythm in iron regulatory protein 2 (IRP2) levels in colon-26 tumors implanted in mice. Our findings suggest that IRP2 regulates the 24-h rhythm of transferrin receptor 1 (Tfr1) mRNA expression post-transcriptionally, by binding to RNA stem-loop structures known as iron-response elements. We also found thatIrp2mRNA transcription is promoted by circadian clock genes, including brain and muscle Arnt-like 1 (BMAL1) and the circadian locomotor output cycles kaput (CLOCK) heterodimer. Moreover, growth in colon-26(Δ19) tumors expressing the clock-mutant protein (CLOCK(Δ19)) was low compared with that in wild-type colon-26 tumor. The time-dependent variation of cellular iron levels, and the proliferation rate in wild-type colon-26 tumor was decreased by CLOCK(Δ19)expression. Our findings suggest that circadian organization contributes to tumor cell proliferation by regulating iron metabolism in the tumor.

• Authors: Fumiyasu Okazaki, Naoya Matsunaga, Hiroyuki Okazaki, Hiroki Azuma, Kengo Hamamura, Akito Tsuruta, Yuya Tsurudome, Takashi Ogino, Yukinori Hara, Takuya Suzuki, Kenji Hyodo, Hiroshi Ishihara, Hiroshi Kikuchi, Hideto To, Hironori Aramaki, Satoru Koyanagi, Shigehiro Ohdo
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 13 Pg. 7017-28 (Mar 25 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 26797126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• ARNTL Transcription Factors
• Arntl protein, mouse
• Cation Transport Proteins
• Per2 protein, mouse
• Period Circadian Proteins
• RNA, Messenger
• Receptors, Transferrin
• Tfrc protein, mouse
• solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
• Iron
• CLOCK Proteins
• Clock protein, mouse
• Iron Regulatory Protein 1
• Iron Regulatory Protein 2

Topics

• ARNTL Transcription Factors (genetics, metabolism)
• Animals
• CLOCK Proteins (deficiency, genetics)
• Cation Transport Proteins (genetics, metabolism)
• Cell Line, Tumor
• Circadian Clocks (genetics)
• Colon (metabolism, pathology)
• Colonic Neoplasms (genetics, metabolism, pathology)
• Gene Deletion
• Gene Expression Regulation, Neoplastic
• Humans
• Iron (metabolism)
• Iron Regulatory Protein 1 (genetics, metabolism)
• Iron Regulatory Protein 2 (genetics, metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Neoplasm Transplantation
• Period Circadian Proteins (genetics, metabolism)
• Protein Multimerization
• RNA, Messenger (genetics, metabolism)
• Receptors, Transferrin (genetics, metabolism)
• Response Elements
• Signal Transduction