fig1

Figure 1. Converging of multiple oncogenic signals initiated from various upstream driver mutations in eliciting transcriptional responses. General transcription factors, mediators and RNA polymerase II assemble to form preinitiation complex to initiate transcription. The process of RNA elongation and termination is regulated by various cyclin-dependent kinases. Blue, yellow, and red circles indicate phosphorylation of the C-terminal domain of RNA Pol II at Ser 5, Ser 7, and Ser 2, respectively, by CDK7 or CDK9. Bromodomain and extra-terminal domain proteins (BET proteins; e.g., BRD4) interact with acetyl-lysines on the chromatin to activate transcription. Nuclear receptors bind to the hormone response element of target genes. Hormone/ligand-bound HRs recruit steroid hormone receptor coactivators (e.g., SRC-3) and other activators such as CBP/p300 and PCAF and together with mediator to form large complexes to further activate transcription. Mutational oncogenic upstream signals relay to converge on the transcription process to alter gene transcription output of proliferation- and differentiation-regulators to promote cancer progression. The expression of critical cancer stem cell transcription factors such as Oct4, Sox2, Nanog and MYC is known to be driven by super-enhancers on the chromatin. Sites in the transcription machinery that could be targeted by inhibitors are shown. NR: nuclear receptor; SRC: steroid hormone nuclear receptor coactivator; HRE: hormone response element; PCAF: CBP/p300-associated factor; PIC: pre-initiation complex; GTFs: general transcription factors; Pol II: polymerase II; CDK7: cyclin-dependent kinase 7; CDK9: cyclin-dependent kinase 9.