Dysregulated Metabolic Cell Cycle Checkpoints in Human Cancer

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DESCRIPTION (provided by applicant): Dysregulated Metabolic Cell Cycle Checkpoints in Human Cancer The decision by a cell to divide or enter quiescence is made in early G1 after mitosis. Cells need instructions from growth factors to continue cycling through G1 into S-phase. In the absence of appropriate growth factor signals, cells enter a resting quiescent state referred to as G0. The site in G1 where growth factor signals are required has been mapped to a site early in G1. This site is commonly referred to as the Restriction Point (R). However, many reports describe R as a site much later in G1 where the cell makes a final commitment to replicate its DNA and divide. This site resembles a site in the yeast cell cycle known as START. However, START is dependent upon nutrient sufficiency rather than growth factors. We are proposing a set of metabolic checkpoints late in G1 that are dependent on nutrient input prior to committing to replicate the genome and dividing. This late G1 cell cycle control site is likely integrated into signals mediated by mTOR - the mammalian target of rapamycin, which senses nutrient and energy sufficiency. We hypothesize that these late G1 cell cycle control sites collectively represent a "Cell Growth" checkpoint where levels of essential nutrients are evaluated prior to committing to doubling in mass and replicating the genome. It is proposed that these metabolic checkpoints, along with R, need to be dysregulated in virtually all human cancers and that complementary genetic changes in human cancer cells cooperate to overcome both R and the Cell Growth checkpoints. This study addresses long-running misconceptions about of G1 cell cycle progression and investigates the feasibility of therapeutic exploitation of dysregulated cell cycle checkpoints in human cancers. The Central Hypothesis of the proposal is that there are Metabolic Cell Cycle Checkpoints late in G1 that can be distinguished from the growth factor-dependent Restriction Point (R). Thus, cells decide first whether they should divide at R, and then prior to replicating the genome, they decide whether they are capable of dividing at a set of Metabolic Cell Growth checkpoints that monitor nutrient sufficiency. It is proposed that mTOR is the final arbiter of whether to commit to replicating the genome and dividing. A series of experiments are proposed that will: 1) Distinguish the impact of growth factors, nutrients and mTOR on G1 cell cycle progression - most significantly, a newly identified lipid-sensitive G1 checkpoint; 2) Distinguish requirements of cells for G1 cell cycle progression when originating from mitosis or from quiescence; and 3) Characterize cell cycle checkpoint(s) mediated by glutamine and evaluate the feasibility of therapeutically exploiting dysregulated checkpoints in human cancer cell lines. Many of the signals that promote progression through late G1 of the cell cycle are commonly referred to as "survival signals" because they suppress apoptotic programs that kick in if the cell is not capable of replicating the genome and dividing. These signals are ideal targets for therapeutic intervention because, in principle, suppression of survival signals leads to either apoptosis or senescence. This study will investigate a proposed set of Metabolic checkpoints in late G1 that are overcome by survival signals in virtually all cancer cells. Therefore, the study will have relevance - and impact - for a large percentage of human cancers because of the need to dysregulate the control of progression through late G1 and avoid the cell death and senescence programs that prevent cancer.