Figure 3.

Cell-to-cell heterogeneity and dynamic variations in Androgen Receptor (AR) activity in an isogenic population. (A) Regulatory circuit formed by interactions among Prostate-associated Gene 4 (PAGE4), Homeodomain-Interacting Protein Kinase 1 (HIPK1), CDC-like Kinase 2 (CLK2), c-Jun, and AR activity—a negative feedback loop. (B) Top panel, in absence of any therapeutic intervention, this negative feedback loop can lead to intracellular oscillations in AR activity. Different colored curves show oscillatory dynamics for two cells in a given isogenic population; these oscillations need not be synchronized, thus, generating cell-to-cell heterogeneity. Bottom panel, upon application of Androgen Deprivation Therapy (ADT) (or periods of AR inhibition during Intermittent Androgen Deprivation Therapy (IAD)), these oscillations can get quenched.