Cell Cycle Regulation by BTG Family Proteins

BTG proteins are novel regulators of transcription that lack an intrinsic transactivation domain, but enhance the recruitment of coactivators. Although little is known about the biological functions of BTG proteins, it is likely that they constitute a family of functionally related genes that are involved in the control of the cell cycle.BTG Family Member-2 (BTG2) is endowed with antiproliferative activity. The expression of BTG2 in cycling cells induces accumulation of hypophosphorylated, growth-inhibitory forms of Retinoblastoma protein(Rb) and lead to G1 arrest through impairment of DNA synthesis. Rb is a nuclear phosphoprotein whose phosphorylation state oscillates regularly during the cell cycle. Hypophosphorylated Rb associates with members of the E2F family of transcription factors, impairing their activity and leading to a cell cycle block in G1. Conversely, the phosphorylation of Rb inactivates its growth suppression activity by freeing E2F molecules, thus enabling them to transactivate genes required for the progression of the cell into S phase and the remainder of the cell cycle. Cyclin-dependent kinases (CDKs) are the molecules responsible for Rb phosphorylation and its consequent inactivation.BTG2 impairs G1-S progression, either by an Rb-dependent pathway through inhibition of CcnD1 transcription, or in an Rb-independent fashion by CcnE down-regulation. The lowered expression of CcnD1 impairs the formation of CcnD1-CDK4. This complex is responsible for the inactivation of Rb through phosphorylation, the preliminary step that triggers the cell cycle entry in G1. BTG2 also controls the G2 checkpoint. Furthermore,BTG2 interacts with CAF1,which influences cell cycle with the transcription factor HOXB9 and PRMT1 that control transcription through histone methylation. The molecular function of BTG2 is still unknown, but its ability to modulate CcnD1 transcription or to synergize with the transcription factor HOXB9 shows that it behaves as a transcriptional co-regulator. In addition to BTG2, BTG1 also binds and positively modulates the transcriptional activity of the HOXB9.BTG1 and BTG2 interact with PRMT1 and increase its methyl-transferase activity. PRMT1 activity is essential for growth factor-induced cell differentiation, and blocking PRMT1 by Box-C domain of BTG1/2 induces apoptosis. The binding of PRMT1 to PP2A which is implicated in several processes including DNA replication, extends to unexplored possibilities the likelihood of a control of cell cycle by BTG2 through modulation of protein methylation.Association of BTG1 and BTG2 with CAF1 modulates transcriptional activity of CAF1. A CDK2-mediated phosphorylation on Ser159 of BTG1 is required for binding to CAF1 and also for the antiproliferative activity of BTG1. CAF1 also binds to CDK4 and CDC2 showing that members of the BTG family regulate the cell cycle by modulating CDK activities through their interaction with CAF1.In conclusion, BTG1 acts as a growth arrest gene responsible for the maintenance of the quiescent state, while BTG2 acts as a negative regulator of the cell cycle by reducing CcnD1 levels, preventing Rb inactivation and reentry into the cycle. This protein family modulates transcription in response to multiple stimuli.