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Continuing proliferation requires regulation of cyclin D1 levels in each cell cycle phase. Growth factors stimulate high levels during G2?phase, which commits the cell to continue through G1?phase with sufficient cyclin D1 to initiate DNA synthesis. Upon entry into S?phase, however, cyclin D1 levels rapidly decline. Our goal is to understand the mechanism and importance of this S-phase suppression. Here, we demonstrate that cyclin D1 levels decline during S?phase due to reduced protein stability, without alterations in the rate of protein synthesis. This decline depends upon Thr 286, since mutation of this site eliminates the normal pattern of cyclin D1 suppression during S?phase. As evidence that phosphorylation of Thr 286 is responsible for this decline, Thr 286 is shown to be more efficiently phosphorylated during S?phase than in other cell cycle periods. Finally, high cyclin D1 levels during S?phase are shown to inhibit DNA synthesis. This inhibitory activity presumably blocks the growth of cells with altered cyclin D1 expression characteristics. Abnormal stimulation of cyclin D1 might result in levels high enough to promote G1/S?phase transition even in the absence of appropriate growth stimuli. In such cells, however, the levels of cyclin D1 would presumably be too high to be suppressed during S?phase, resulting in the inhibition of DNA synthesis.Oncogene (2005) 24, 2599-2612. doi:10.1038/sj.onc.1208326 Published online 21 February 2005 [ABSTRACT FROM AUTHOR]