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p27Kip1 and Cyclin Dependent Kinase 2 Regulate Passage Through the Restriction Point
Masahiro Hitomi, Ke Yang, Yang Guo, Jonathan Fretthold, Jyoti Harwalkar and Dennis Stacey
volume 5 | issue 19
1 october 2006Pages: 2281 - 2289
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When quiescent cells are stimulated to re-enter the cell cycle, growth factors are required only until the restriction point in G1 phase. After this point the cell no longer requires growth factors, proliferative signaling molecules, or even protein synthesis in order to initiate DNA synthesis, which starts several hours later. Consequently, understanding the molecular nature of the restriction point constitutes one of the major goals in studies of growth regulation. We recently demonstrated that p27Kip1 (p27) regulates passage through G1 phase in actively proliferating cultures, and initiated these studies to determine if it is also involved in passage through the restriction point following stimulation of quiescent cells. In support of this suggestion, we found that passage through the restriction point requires mitogen-dependent suppression of the high p27 levels normally present in quiescent cells. Moreover, as the culture progresses to mid-G1 phase, the proportion of cells that pass the restriction point is increased by artificial suppression of p27 levels, while this proportion is reduced by elevation of p27 levels. p27 performs this critical function by regulating the subsequent activating phosphorylation of cyclin dependent kinase (CDK)2, which we also show is necessary for and closely associated with the initiation of DNA synthesis. We conclude that the p27 expression level at mid-G1 phase determines when a cell passes through the restriction point, and does so by regulating subsequent CDK2 activation.
Authors
Masahiro Hitomi
The Lerner Research Institute
Ke Yang
The Lerner Research Institute
Yang Guo
The Lerner Research Institute
Jonathan Fretthold
The Lerner Research Institute
Jyoti Harwalkar
The Lerner Research Institute
Dennis Stacey
The Lerner Research Institute
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.