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RESEARCH PAPER
1 Department of Biochemistry, 2 Department of Cellular Biochemistry, and 3 The Lautenberg Center for General and Tumor Immunology, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
The regulated phosphorylation of ribosomal protein (rp) S6 has attracted much attention since its discovery in 1974, yet its physiological role has remained obscure. To directly address this issue, we have established viable and fertile knock-in mice, whose rpS6 contains alanine substitutions at all five phosphorylatable serine residues (rpS6P-/-). Here we show that contrary to the widely accepted model, this mutation does not affect the translational control of TOP mRNAs. rpS6P-/- mouse embryo fibroblasts (MEFs) display an increased rate of protein synthesis and accelerated cell division, and they are significantly smaller than rpS6P+/+ MEFs. This small size reflects a growth defect, rather than a by-product of their faster cell division. Moreover, the size of rpS6P-/- MEFs, unlike wild-type MEFs, is not further decreased upon rapamycin treatment, implying that the rpS6 is a critical downstream effector of mTOR in regulation of cell size. The small cell phenotype is not confined to embryonal cells, as it also selectively characterizes pancreatic 
-cells in adult rpS6P-/- mice. These mice suffer from diminished levels of pancreatic insulin, hypoinsulinemia, and impaired glucose tolerance.
[Keywords: Knock-in mouse; TOP mRNAs; translational control; cell size; glucose intolerance; hypoinsulinemia]
Received May 15, 2005; revised version accepted July 20, 2005.
4 Corresponding author.
E-MAIL meyuhas{at}cc.huji.ac.il; FAX 972-2-6757379.
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