Year: 2006
Type: article
Abstract: When quiescent cells are stimulated to reenter the cell cycle, growth factors are required only until the restriction point in G(1) 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 G(1) 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-G(1) 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-G(1) phase determines when a cell passes through the restriction point, and does so by regulating subsequent CDK2 activation.
Source: Cell Cycle
DOI: 10.4161/cc.5.19.3318
Authors: Masahiro Hitomi, Ke Yang, Yang Guo, Jonathan Fretthold, Jyoti Harwalkar, Dennis Stacey
Institutions: Cleveland Clinic, Cleveland Clinic Research
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2082655977