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Mentions: Cells arrested by CKI overexpression formed a clade that was distinct from the clade comprised of cells arrested by extracellular signals (Figure 8A). The transcriptional pattern induced by CKI overexpression did not closely resemble the quiescent state induced by any particular extracellular signal. Only a small proportion of all of the genes regulated by all signals or an individual signal were also regulated by CKIs, with the greatest overlap among genes downregulated by all signals (Figure 8B–8E). Indeed, although downregulated quiescence program genes were likely also to be downregulated by CDK inhibition, many upregulated genes in the quiescence program were not induced by CDK inhibition. More precisely, genes regulated by four different anti-proliferative signals were extremely likely (78%) to be regulated in a fifth condition. Among genes that were consistently downregulated 2-fold in all of the quiescent states, a significant fraction (54%) was also downregulated in cells arrested by p21 and p27 (Table 3). These commonly regulated genes clustered into the functional category of cell-cycle regulators. Thus, there was a self-reinforcing component to cell-cycle arrest, in the sense that CDK inhibition caused downregulation of additional genes that also directly affected the cell cycle.
A New Description of Cellular QuiescenceQuiet Time: Gene Program Prevents Division but Keeps Cells at the Ready
Bottom Line: We further demonstrate that one mechanism by which the reversibility of quiescence is insured is the suppression of terminal differentiation.Expression of the quiescence program was not simply a downstream consequence of exit from the cell cycle, because key parts, including those involved in suppressing differentiation, were not recapitulated during the cell cycle arrest caused by direct inhibition of cyclin-dependent kinases.These studies form a basis for understanding the normal biology of cellular quiescence.
Affiliation: Department of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. firstname.lastname@example.org
Abstract: Cellular quiescence, defined as reversible growth/proliferation arrest, is thought to represent a homogenous state induced by diverse anti-mitogenic signals. We used transcriptional profiling to characterize human diploid fibroblasts that exited the cell cycle after exposure to three independent signals--mitogen withdrawal, contact inhibition, and loss of adhesion. We show here that each signal caused regulation of a unique set of genes known to be important for cessation of growth and division. Therefore, contrary to expectation, cells enter different quiescent states that are determined by the initiating signal. However, underlying this diversity we discovered a set of genes whose specific expression in non-dividing cells was signal-independent, and therefore representative of quiescence per se, rather than the signal that induced it. This fibroblast "quiescence program" contained genes that enforced the non-dividing state, and ensured the reversibility of the cell cycle arrest. We further demonstrate that one mechanism by which the reversibility of quiescence is insured is the suppression of terminal differentiation. Expression of the quiescence program was not simply a downstream consequence of exit from the cell cycle, because key parts, including those involved in suppressing differentiation, were not recapitulated during the cell cycle arrest caused by direct inhibition of cyclin-dependent kinases. These studies form a basis for understanding the normal biology of cellular quiescence.
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