Selective suppression of growth factor-induced cell cycle gene expression by Na+/H+ antiport inhibitors

• Published in: The Journal of biological chemistry Vol. 267; no. 27; pp. 19043 - 19046
• Main Authors: G Vairo, B G Cocks, E J Cragoe, Jr, J A Hamilton
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Biochemistry and Molecular Biology 25.09.1992
• Subjects: Amiloride - analogs & derivatives; Amiloride - pharmacology; Animals; Biological and medical sciences; Carrier Proteins - antagonists & inhibitors; Cell Cycle - drug effects; Cell physiology; Cells, Cultured; Cyclins - genetics; DNA - biosynthesis; DNA Replication - drug effects; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; In Vitro Techniques; Macrophage Colony-Stimulating Factor - antagonists & inhibitors; Macrophages - cytology; Macrophages - physiology; Mice; Mice, Inbred Strains; Molecular and cellular biology; Nuclear Proteins - genetics; Proliferating Cell Nuclear Antigen; Responses to growth factors, tumor promotors, other factors; RNA - biosynthesis; RNA, Messenger - genetics; Sodium-Hydrogen Exchangers; Vertebrata; Mammalia; Ribonucleotide reductase; Mouse; Enzyme; Rodentia; Cell cycle; Enzyme inhibitor; Gene expression; Colony stimulating factor
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(18)41736-X

Activation of Na+/H+ exchange activity is a ubiquitous response to growth factors and has been implicated in the mitogenic response. Little is known of how the antiport influences events in the nucleus which ultimately control the cell cycle. Using potent Na+/H+ exchange inhibitors we show for normal mouse bone marrow-derived macrophages that this activity is required for the colony-stimulating factor-1-induced gene expression of the M1 and M2 subunits of ribonucleotide reductase, an enzyme critical for DNA synthesis. Suppression of M1 and M2 mRNA levels occurred when the inhibitors were added up to 8 h after the growth factor, mirroring their ability to prevent entry into S phase at similar times. Antiport activity was not required for the induction of other genes associated with cell cycle progression including proliferating cell nuclear antigen and the G1 cyclin, CYL1. These results highlight the differential expression of various cell cycle-associated genes and demonstrates that non-coordinate regulation of CYL1 cyclin and DNA synthesis gene expression can occur. The selective dependence of ribonucleotide reductase subunit gene expression on Na+/H+ exchange activity may provide a biochemical basis for the requirement of persistent antiporter activity during G1 for subsequent entry into S phase.