Abstract
The cell cycle is strictly programmed with control mechanisms that dictate order in cell cycle progression to ensure faithful DNA replication, whose deviance may lead to cancer. Checkpoint control at the G1/S, S/G2 and G2/M portals have been defined but no statutory time-programmed control for securing orderly transition through S phase has so far been identified. Here we report that in normal cells DNA synthesis is controlled by a checkpoint sited within the early part of S phase, enforced by the βGBP cytokine an antiproliferative molecule otherwise known for its oncosuppressor properties that normal cells constitutively produce for self-regulation. Suppression of active Ras and active MAPK, block of cyclin A gene expression and suppression of CDK2-cyclin A activity are events which while specific to the control of a cell cycle phase in normal cells are part of the apoptotic network in cancer cells.
Highlights
Checkpoint mechanisms that in normal mammalian cells dictate order and timing during progression from one cell cycle phase to the next to ensure that events critical to genome replication are completed with fidelity have been attracting special interest as perturbations of the related biochemical processes may lead to biological disorders, which include cancer[1,2,3]
To determine whether under normal growth conditions S phase is under checkpoint control we used secondary murine embryonic fibroblasts, chosen as a paradigm of normal cells cultured to maintain a high degree of population uniformity while undergoing transition through the cell cycle[10] and have made use of the recombinant form of the human βGBP molecule, which is an autocrine negative growth effector
Parallel analysis of untreated cells (Fig. 1a left column and 1b left column) and of cells treated with βGBP (Fig. 1a right column and 1b right column) shows that in marked difference with the control population which had transposed into G1 upon completion of a full cycle, DNA synthesis and cell cycle progression, that in the treated cells had ab initio progressed in parallel with the controls, had come to a halt at hour 24
Summary
Checkpoint mechanisms that in normal mammalian cells dictate order and timing during progression from one cell cycle phase to the next to ensure that events critical to genome replication are completed with fidelity have been attracting special interest as perturbations of the related biochemical processes may lead to biological disorders, which include cancer[1,2,3]. RESULTS To determine whether under normal growth conditions S phase is under checkpoint control we used secondary murine embryonic fibroblasts, chosen as a paradigm of normal cells cultured to maintain a high degree of population uniformity while undergoing transition through the cell cycle[10] and have made use of the recombinant form of the human βGBP molecule, which is an autocrine negative growth effector.
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