The effect of rapamycin on DNA synthesis in multiple tissues from late gestation fetal and postnatal rats

• Published in: American Journal of Physiology: Cell Physiology Vol. 295; no. 2; pp. C406 - C413
• Main Authors: Sanders, Jennifer A, Lakhani, Alisha, Phornphutkul, Chanika, Wu, Ke-Ying, Gruppuso, Philip A
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.08.2008
• Subjects: Animals; Animals, Newborn; Apoptosis; Bromodeoxyuridine - metabolism; Cell cycle; Cell growth; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Proliferation - drug effects; Cells; Deoxyribonucleic acid; DNA; DNA - biosynthesis; DNA Replication - drug effects; Fetal Weight - drug effects; Growth, Differentiation, and Apoptosis; Hepatectomy; Immunosuppressive Agents - pharmacology; Ki-67 Antigen - metabolism; Liver - embryology; Liver - metabolism; Liver - physiology; Liver Regeneration - drug effects; Phosphorylation - drug effects; Protein Kinases - metabolism; Protein synthesis; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 - metabolism; Ribosomal Protein S6 Kinases - metabolism; Rodents; Signal Transduction - physiology; Sirolimus - pharmacology; TOR Serine-Threonine Kinases
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00450.2007

Division of Pediatric Endocrinology and Metabolism, Rhode Island Hospital, and the Warren Alpert Medical School of Brown University, Providence, Rhode Island Submitted 28 September 2007 ; accepted in final form 9 June 2008 Rapamycin is a potent antiproliferative agent that arrests cells in the G1 phase of the cell cycle through a variety of mechanisms involving the inhibition of the mammalian target of rapamycin (mTOR) pathway. The majority of normal cells in culture are sensitive to the cytostatic effects of rapamycin, whereas the growth of many malignant cells and tumors is rapamycin resistant. We had shown previously that hepatic DNA synthesis in the late gestation rat fetus is rapamycin resistant even though signaling through the mTOR/S6 kinase (S6K) pathway is attenuated. On the basis of this finding, we went on to characterize the response to rapamycin in a spectrum of tissues during late gestation and the early postnatal period in the rat. We found that rapamycin had no effect on DNA synthesis in major organs such as heart, intestine, and kidney in the fetal and early postnatal rat despite a marked attenuation in the phosphorylation of ribosomal protein S6. In contrast, the proliferation of mature hepatocytes during liver regeneration was highly sensitive to rapamycin. These data indicate that basal cellular proliferation in a wide variety of tissues is rapamycin resistant and occurs independently of mTOR/S6K signaling. Furthermore, the well-characterized effects of rapamycin in tissue culture systems are not recapitulated in the asynchronous cell proliferation that accompanies normal growth and tissue remodeling. proliferation; mammalian target of rapamycin; growth Address for reprint requests and other correspondence: J. A. Sanders, Dept. of Pediatrics, Rhode Island Hospital, 593 Eddy St., Providence, RI 02903 (e-mail: Jennifer_Sanders{at}brown.edu )