Figure 1.
Schematic diagram outlining our hypothesis.
Table 1.
Enriched GO terms for the core group that were statistically significant at the 0.1 level.
Table 2.
Enriched GO terms for the transient group that were statistically significant at the 0.1 level.
Figure 2.
DMSO upregulates the tumor suppressor protein PTEN [15] in HL-60 cells. This increase in PTEN expression and activity is brought about by the activation of NF-κB. PTEN is a lipid phosphatase that is located in the cytoplasm and one of its primary roles is to dephosphorylate PIP3, a product of PI3K. The upregulation of PTEN results in a perturbation of the PI3k/Akt pathway, specifically the reduction in Akt phosphorylation levels and hence decreasing the amount of activated Akt. Normally activated Akt leads to phosphorylation of FOXO3, a member of the forkhead transcription factor family and this sets off further pathways that promote cell survival. However, inactive FOXO3 is able to translocate to the nucleus where it acts as a transcription factor, binding to cis-DNA elements and causing an increase in the gene expression of p27 [16]. The p27 protein inhibits the cyclin-dependent kinase complex Cyclin E and CDK2 which controls the G1 to S phase transition.
Figure 3.
ATRA is able to diffuse freely across the cell membrane. A pair of cellular retinoic acid binding proteins act as cell surface receptors for retinoids however these have been shown to be dispensable in retinoic-acid signaling [21]. ATRA binds to a family of nuclear hormone receptors called retinoic-acid receptors (RARs). There are three subtypes of the RAR family, these are encoded by different genes and denoted RAR-α, RAR-β, RAR-γ. Collins et al [22] demonstrated that in HL-60 cells, ATRA induced granulocytic differentiation by binding RAR-α directly. RAR-α binds to specific cis-acting DNA sites, known as retinoic-acid response elements (RAREs). These RAREs are located in the promoter sequences of specific genes that are targets of RAR-α. In order to bind DNA efficiently, RARs must however form heterodimers with a second family of nuclear hormone receptors, the retinoid X receptors (RXRs), of which there are three subtypes: RXR-α, RXR-β, RXR-γ. Both RXRs and RARs function as ligand-dependent transcription factors. One of the RAR-target genes whose expression is upregulated is the cell cycle protein p21 [23]. p21 inhibits the cyclin dependent kinase complex Cyclin E and CDK2. In this way, ATRA induces cell cycle arrest at the G1 to S phase transition checkpoint.
Figure 4.
Gene expression mosaics of the ATRA and DMSO-stimulated time course data.
The expression mosaics for the ATRA and DMSO-stimulated time course data capture spatial patterns in the data as the system iterates through the time series. These images are a graphical representation of dynamic expression changes in the data, clustered using a self-organizing map algorithm (SOM). We show how the overall expression trajectories for the ATRA and DMSO-stimulated data can be divided into components defined by the core and transient set of genes. Red denotes extreme positive log expression ratios, blue denotes extreme negative log expression ratios.