The Checkpoints Parent-Teen Driving Agreement (Checkpoints P-TDA) was designed so that parents could initially impose strict limitations on teen driving in high-risk driving conditions (e.g., at night and with teen passengers) and gradually increase driving privileges over time as teens demonstrate responsible driving behavior.
Some of the new categories for which targets at P > 0.95 show enrichment include chromatin assembly/disassembly (p = 1e-10), septin checkpoint (p = 2.7e-3), and lipid metabolism (p = 8.4e-4).
Cell cycle progression and checkpoint control gene clusters were maximally enriched in the RISC (B) at 36 h (cluster 3: mitosis p < 1.92E-10) and 48 h (cluster 12, DNA replication checkpoint, p < 2.71E-07).
These observations are consistent with the prediction that genes differentially expressed after miR-128 transfection are enriched for genes involved in "Cell cycle: The metaphase checkpoint" (p = 1.01×10-11, Table 2B) and "Cell cycle_Spindle assembly and chromosome separation" (p = 2.75×10-7, Table 2B).
CD133+ AT/RT cells preferentially activate DNA damage checkpoint (p-ATM, p-RAD17, and p-CHK2) and antiapoptotic (BCL-2 and BCL-XL) genes in response to IR (Figure 5; Figure S1 & Figure S2).
Fourth, the passenger genes are enriched with GO categories of caspace activation (hyper-geometric p-value ≤ 0.001), cyclin-dependent kinase activity (p-value ≤ 0.0025), cell cycle arrest (p-value ≤ 0.0069), and pathways of TP53 signaling (p-values ≤ 1.55 × 10-5,≤ 4.14 × 10-4), and G2/M checkpoint (p-value ≤ 0.0012) (Table 5).
Consistent with our microarray findings, the activating phosphorylation of the checkpoint proteins, p-ATM, p-RAD17, and p-CHK2, was significantly higher in IR-treated CD133+ than in IR-treated CD133− (Figure 6A), indicating that CD133+ AT/RT cells display greater checkpoint activation in response to DNA damage.
In the list of the most overexpressed genes at relapse, the most significant GeneGo Pathway Map was the 'Cell cycle: the metaphase checkpoint' pathway (P value=3.94E−10), including genes such as AURORA Kinase A (AURKA), AURORA Kinase B (AURKB), SURVIVIN (BIRC5), BUB1, RAD51, CENPA, INCENP and PLK1 (Supplementary Figure S4).
Other related predominant processes include those pertaining to DNA damage checkpoint (8 genes, p = 5380 × 10-4, not shown), protein transport (38 genes, p = 0.0034), and post-translational protein modification (53 genes, p = 0.0045, especially those involve in phosphorylation (37 genes, p = 0.0124)).
In addition, low levels of TP53 gene expression correlated to increased interconnectivity between the two mitotic modules in luminal samples, and TP53-mutated luminal samples showed elevated activity of the mitotic checkpoint and progression modules (P = 5*10-4 and P = 9*10-4, t-tests).
