BCL2 family in DNA damage and cell cycle control

Abstract

Individual BCL2 family members couple apoptosis regulation and cell cycle control in unique ways. Antiapoptotic BCL2 and BCL-x L are antiproliferative by facilitating G0. BAX is proapoptotic and accelerates S-phase progression. The dual functions in apoptosis and cell cycle are coordinately regulated by the multi-domain BCL2 family members (MCL-1) and suggest that survival is maintained at the expense of proliferation. The role of BH3-only molecules in cell cycle is more variable. BAD antagonizes both the cell cycle and antiapoptotic functions of BCL2 and BCL-x L through BH3 binding. BID has biochemically separable functions in apoptosis and S-phase checkpoint, determined by posttranslational modification. p53-induced PUMA is known only to have apoptotic function. Inhibition of apoptosis is oncogenic, whereas promotion of cell cycle arrest is tumor suppressive. Paradoxically, selected BCL2 family members can be both oncogenic and tumor suppressive. Which of the dual functions predominates is lineage specific and context dependent.

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

“…The cell death regulators of the BCL-2 family were previously shown to exert cell cycle effects. 45 To investigate whether BAD alters CSC's cell cycle progression, we cultured control or BADdepleted cells in sphere-forming medium for 7 days. Cell cycle analysis revealed that there was 40% reduction in cells with S/G2 fraction (DNA content 2N-4N) in BAD-depleted spheres compared with control spheres (Figure 6a).…”

Evaluation of anti–apoptotic activity of different dietary antioxidants in renal cell carcinoma against hydrogen peroxide

“…Here the increase of bcl-2 expression is in coherence with above mentioned obervation and could be correlated like, bcl-2 mediated reaction leads the cells to make them resistant to oxidant and oxidant-induced apoptosis [24] . The antiapoptotic function and its efficiency are controlled by the bcl-2 family members, which function partly by interacting physically with one another at mitochondrial level [31] . Here, our findings have shown the importance and role of bcl-2 over the H 2 O 2 -induced apoptosis and its prevention by antioxidants in renal cell carcinoma cells.…”

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…Exploiting the endogenous cell death machinery to reactivate the apoptotic cell death pathway may be achieved by antagonizing prosurvival Bcl2 family members directly or by inhibiting apoptosis downstream of Bcl2 induction. Modulation of Bcl2 family members using small-molecule drugs in tumor cells, which may carry one or more such dysregulated signaling pathways, may present an effective way to sensitize tumor cells to combination therapies (Labi et al, 2006;Walensky, 2006;Zinkel et al, 2006;Reed, 2006b). Small-molecule inhibitors targeting Bcl2 family proteins such as the BH3-only peptidomimetic drugs (for example, ABT-737) are under evaluation in pre-clinical and clinical trials with the promise of single-agent activity against numerous cancers (Adams and Cory, 2007;Zhang et al, 2007;Cragg et al, 2009).…”