BCL-2 in the crosshairs: tipping the balance of life and death

Abstract

The discovery of B-cell lymphoma-2 (BCL-2) over 20 years ago revealed a new paradigm in cancer biology: the development and persistence of cancer can be driven by molecular roadblocks along the natural pathway to cell death. The subsequent identification of an expansive family of BCL-2 proteins provoked an intensive investigation of the interplay among these critical regulators of cell death. What emerged was a compelling tale of guardians and executioners, each participating in a molecular choreography that dictates cell fate. Ten years into the BCL-2 era, structural details defined how certain BCL-2 family proteins interact, and molecular targeting of the BCL-2 family has since become a pharmacological quest. Although many facets of BCL-2 family death signaling remain a mechanistic mystery, small molecules and peptides that effectively target BCL-2 are eliminating the roadblock to cell death, raising hopes for a medical breakthrough in cancer and other diseases of deregulated apoptosis.

Phospho-ΔNp63α is a key regulator of the cisplatin-induced microRNAome in cancer cells

“…[5][6][7][8][9][10][11][12] CIS has been shown to increase the expression and activity of HIPK2, whose activation subsequently leads to CIS-dependent apoptosis through TP53 phosphorylation at Serine-46 (S46-p-TP53), which in turn activates certain apoptotic gene promoters and modulates the TP53-dependent protein-protein interactions. [34][35][36] Forced HIPK2 expression in U2OS cells increased the apoptotic response to CIS and potentiated the tumor suppressive activity of TP53 and TP73 through their protein-protein interactions.…”

“…[3][4][5][6][7] When induced, TP53, TP63, and TP73 alter the transcription of a large set of downstream target genes, controlling cell-cycle arrest, cell death, increased DNA repair, inhibition of angiogenesis, and so on. [8][9][10][11][12] MicroRNA species (miRNAs) are small 18-24-nucleotide non-coding RNAs that act through the RNA interference pathway and repress target gene expression largely by modulating translation and mRNA stability. 13,14 miRNA precursors (pri-miRNAs) are processed in the nucleus, and the hairpin products are then cleaved by the double-stranded ribonuclease, DICER1, in the cytoplasm to generate mature miRNAs.…”

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).…”

The mitochondrial serine protease HtrA2/Omi cleaves RIP1 during apoptosis of Ba/F3 cells induced by growth factor withdrawal

“…To verify whether apoptosis induced in Ba/F3 cells by IL-3 deprivation proceeds through the mitochondrial pathway, we used Bcl-2 overexpressing Ba/F3 cells. The antiapoptotic Bcl-2 protein is known to block the mitochondrial apoptotic pathway by preventing the release of mitochondrial pro-apoptotic proteins, such as cytochrome c and HtrA2/Omi [28]. Kinetics of Ba/F3 apoptosis in response to IL-3 depletion was determined by measuring DNA hypoploidy ( Figure 1A) and plasma membrane permeabilization ( Figure 1B).…”