# The BCL-2 database, Act 2: moving beyond dualism to diversity and pleiotropy

Aouacheria

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Aouacheria. The BCL-2 database, Act 2: moving beyond dualism to diversity and pleiotropy. Cell Death & Disease, 2014, 5 (1), 10.1038/cddis.2013.511. hal-05091878

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Correspondence

# The BCL-2 database, Act 2: moving beyond dualism to diversity and pleiotropy

A Aouacheria* , 1

*Cell Death and Disease* (2014) **5**, e981; doi:10.1038/cddis.2013.511; published online 2 January 2014

**Subject Category:** Cancer

Dear Editor,

BCL2 was discovered almost 30 years ago as part of a
translocation (t14;18) in human B-cell lymphoma.<fnref n="1" /> Unique
to all other oncogenes known to that date, the product of this
gene turned out to act as a cytoprotective factor rather than
as a cell growth promoter,² providing a remarkable first
in biology. The human BCL-2 protein was also the first
identified component of the cellular machinery of apoptosis.
Evolutionary conservation of this machinery became
evident when it was realized that *Caenorhabditis elegans*
was containing an antiapoptotic Bcl-2-like protein, CED-9.³
Soon thereafter, it also became clear that BCL-2 was
belonging to a large group of proteins that can either repress
(such as BCL-xL or MCL-1) or promote (e.g. BAX or BAK)
apoptosis. The concept (first issued by Stanley Korsmeyer⁴)
that the ratio between BCL-2 and BAX, and more generally
between proapoptotic members and prosurvival members
(the so-called ‘rheostat’ hypothesis), can determine cell
survival or death after an apoptotic stimulus had a deep
and sustained influence on the field. Most of the works
performed on BCL-2 family proteins and most of the reviews
written on the subject so far are rooted in this epistemo-
logical and ontological dualism, which has proven immensely
useful in understanding the basic aspects of apoptosis
regulation by BCL-2 family members. Yet, a number of
studies have highlighted the need to transcend this
simplistic dualism. These studies may be grouped into four
main branches: (a) the demonstration that a distinct
subclass of proapoptotic proteins sharing a single region
of sequence similarity with BCL-2, termed the BH3 motif,
act *upstream* of the various ‘multi-BH’ BCL-2 homologs;
(b) evidence showing that at least certain BCL-2 proteins
could be bi-functional, shifting from a cytoprotective to a
cytotoxic activity and *vice versa*, depending on changes in
the expression level, cell types, alternative splicing and
post-translational modifications; (c) the findings that BCL-2
proteins, which act at the mitochondrial level to regulate
apoptosis, could also exert functions at non-mitochondrial
sites and, more importantly, could play physiological
(non-apoptotic) roles in cells uncommitted to death, such as
regulation of mitochondrial dynamics, metabolism and calcium

homeostasis, or during development;⁵ (d) phylogenomics
and bioinformatics studies documenting the important degree
of divergence between BCL-2 homologous sequences,⁶
and the potential huge number of BH3-containing proteins
(due to the poor definition of the BH3 signature).⁷ Collectively,
these different points suggest that a major shift of paradigm is
taking place in our understanding of BCL-2 proteins, moving
from a notion of opposition (anti- versus proapoptotic
members) to a notion of diversity (in sequence, structure,
function, evolution) and pleiotropy (i.e., vital roles unrelated to
cell death regulation).⁸

Taking this paradigm shift from a phylogenomics perspec-
tive, we have previously reported that duplications played a
prominent role in the divergent evolution of BCL-2
homologous genes and contributed to the generation of
substantial lineage-specific diversity in the BCL-2 comple-
ment of extant metazoans.⁶ Contrary to cellular BCL-2
homologous proteins, BH3-only proteins are evolutionarily
unrelated to each other (i.e., they have not arisen from a
common ancestor by duplication). Intriguingly, more than 30
cellular and viral proteins have recently been claimed to
contain ‘BH3-like’ motifs,⁷ suggesting that the distribution of
BH3-containing proteins might be broader than initially
conceived. The large and heterogeneous mixture of proteins
forming the contemporary BCL-2 group poses major
challenges to researchers trying to investigate their
structure–function relationships. As an attempt to help
address this issue, we have built a novel version of the
BCL-2 Database (http://bcl2db.ibcp.fr/). This novel version
of BCL2DB represents an effort toward providing a more
global picture of BCL-2 proteins, with the objective of
facilitating the reframe from dualism to multiplicity.

**Conflict of Interest**

The author declares no conflict of interest.

**Acknowledgements.** This work was supported by La Ligue Contre le Cancer (Comité de Saône-et-Loire) and Région Rhône-Alpes (CIBLE program). BCL2DB version 2 was developed by Valentine Rech de Laval, Professor Gilbert Deléage, Dr. Christophe Combet and the author on the PRABI platform funded by GIS IBiSA-AO 2009. We wish to acknowledge and thank the past, present and

<footnote n="1">¹Molecular Biology of the Cell Laboratory, Ecole Normale Supérieure de Lyon, LBMC UMR 5239 CNRS—UCBL—HCL—ENS Lyon, 46 Allée d'Italie, 69364 Lyon, France</footnote>

<footnote>*Corresponding author: A Aouacheria, Molecular Biology of the Cell Laboratory, Ecole Normale Supérieure de Lyon, LBMC UMR 5239 CNRS—UCBL—HCL—ENS Lyon, 46 Allée d'Italie, 69364 Lyon, France. Tel: +33 4 26 23 59 43; Fax: +33 4 26 23 59 01; E-mail: abdel.aouacheria@ens-lyon.fr</footnote>
future members of our Scientific Advisory Board for their thoughtful comments and
suggestions.

1. Cleary ML, Smith SD, Sklar J. *Cell* 1986; **47**: 19–28.

2. Vaux DL, Cory S, Adams JM. *Nature* 1988; **335**: 440–442.

3. Hengartner MO, Horvitz HR. *Cell* 1994; **76**: 665–676.

4. Korsmeyer SJ et al. *Semin Cancer Biol* 1993; **4**: 327–332.

5. Hardwick JM, Soane L. *Cold Spring Harb Perspect Biol* 2013; **5**: 2.

6. Aouacheria A, Brunet F, Gouy M. *Mol Biol Evol* 2005; **22**: 2395–2416.

7. Aouacheria A et al. *Trends Cell Biol* 2013; **23**: 103–111.

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