Stopping cells from dividing

than inhibiting cell division? The quest to identify means to stop cells from proliferating has driven generations of researchers to investigate the mechanisms regulating the cell division cycle. The cell cycle consists of several phases. Progression from one phase to the next depends on the activity of specific proteins. In order to pass the checkpoints between two phases, several classes of proteins are required. These regulators include transcription factors, kinases, phosphatases, and proteins acting through complex formation. The synthesis of these proteins-particularly transcriptional control of their genes-constitutes an important mode to regulate cell division. A key regulator of the cell cycle is the tumor suppressor p53. It is a transcription factor which functions by activating genes [1]. The cyclin-dependent kinase inhibitor p21/CDKN1A gene was the first identified p53 transcriptional target. In addition to genes being activated, many genes become downregulated upon p53 activation. For transcriptional repression by p53 several-often conflicting-mechanisms have been proposed [2]. In fact, there is evidence that p53-mediated downregulation is always indirect [3]. Transcriptional repression by p53 appears to occur without direct contact of p53 to its target genes [3]. With Cyclin B2 as the first example, a novel pathway was suggested which explains the mechanism of transcriptional repression by p53 [4]. Specifically, this pathway is not initiated by repression but by p53 transcriptionally activating p21/CDKN1A. The p21/CDKN1A protein then inhibits Cyclin/CDK kinase complexes (Figure 1). This causes hypophosphorylation of the pRB-related pocket proteins p130 and p107. Their reduced phosphorylation shifts the equilibrium from the activating MMB to the repressing DREAM complex. Binding of DREAM to CHR promoter elements finally downregulates target genes [4]. CDE sites four nucleotides upstream of CHR elements can support binding of DREAM to DNA (Figure 1). Taken together, stimulation of the p53-p21-Cyclin/CDK-DREAM-CDE/CHR pathway causes transcriptional downregulation of target genes after p53 has been activated [4]. After resolving this pathway for one gene, the main question was whether this indirect mechanism of p53-dependent transcriptional repression applies also to Editorial other genes. In a recent report published in Oncotarget, three genes important for cell cycle regulation have been shown to be controlled by the p53-p21-Cyclin/CDK-DREAM-CDE/CHR pathway [5]. Survivin (BIRC5), CDC25C, and PLK1 represent genes that had been previously examined in several reports for their transcriptional control during the cell cycle and in regard to their response to p53 activation [5]. However, incomplete and partially contradicting observations had been published specifically on transcriptional regulation of …