Springer, Encyclopedic Reference Of Cancer (2001) Ocr 7.0 Lotb.pdf

100 BCL-2
with another adaptor termed 14-3-3, and thus
inactivated. In the absence of growth/survival
factors (such as in ! IL-3 deprivation of IL-3-dependent
hematopoietic cell lines), Raf-1 is not
activated and the non-phosphorylated Bad is
able to perform its pro-apoptotic function. Another
example of the Bcl-2 function as an adaptor
protein derives from studies on CED-4, a
pro-apoptotic protein from the nematode Caenorhabitis
elegans. In this case, Bcl-2 binds to
and sequesters CED-4, thus preventing CED-
4-dependent activation of cytosolic caspases,
a family of cell death cysteine proteases. Conversely,
pro-apoptotic members of the Bcl-2 family
heterodimerize with Bcl-2, as if competing
with CED-4, thus causing its displacement from
Bcl-2. Set free from mitochondrial confinement,
CED-4 returns to the cytosol and activates cell
death proteases. Bcl-2 family members compete
with each other, and the final outcome (cell
death or survival) clearly depends upon the
anti-apoptotic:pro-apoptotic protein ratio.
Bcl-2 has also been reported to interact with
chromosomes, thus leading to hypotheses suggesting
a role in the regulation of the cell cycle.
In a number of transformed human cell lines,
Bcl-2 localizes on chromosomes in a cell cycledependent
manner, accumulating in prophase
and metaphase and disappearing during telophase.
Regulation
Whether through its function as a channel protein
or as an adaptor/docking protein, the final
result on cell fate, however, depends upon the
level of expression of Bcl-2. Consistently, Bcl-2
expression control has been the object of numerous
studies of transcriptional, translational
and post-translational regulation. Over-expression
of Bcl-2 in human cancer prevents the
transformed cells from undergoing apoptosis
so that they proliferate accumulating mutations,
develop resistance to anti-cancer treatments
and progress towards a more malignant
phenotype. However, surprisingly little is
known about the molecular basis of this overexpression.
Thus, sequencing of the Bcl-2
coding region in Bcl-2-over-expressing tumors
revealed a notable absence of mutations. An-
other level of Bcl-2 regulation is concerned
with mRNA stabilization. Bcl-2 mRNA is characterized
by a conserved adenine- and uracilrich
element (AU-rich element, ! ARE) present
in the untranslated region (3 0 -UTR). AREs have
also been described in the 3 0 -UTR of numerous
mRNA of cytokines and proto-oncogenes.
AREs comprise a major group of cis-acting elements
that target these mRNAs for rapid degradation.
AREs exert a post-transcriptional control
of gene expression by interacting with cytoplasmic
and nuclear RNA binding proteins,
and ARE deletions are associated with the activation
of proto-oncogenes such as c-fos and
c-myc. Consistently, protein kinase C, the target
of numerous tumor promoters, inactivates the
destabilizing function of Bcl-2 ARE, leading to
increased Bcl-2 expression and protection from
apoptosis. Thus, transformed cells with increased
level of diacylglycerol that activates
protein kinase C, show increased resistance
to the killing effects of ionizing radiations.
However, apoptotic stimuli enhance the destabilizing
function of Bcl-2 ARE, thus being responsible
for Bcl-2 down-regulation during
apoptosis.
Bioactivity
Oncogenes and tumor suppressor genes modulate
Bcl-2 expression with profound results on
death or survival of neoplastic cells. The tumor
suppressor gene p53 can induce apoptotic cell
death by down-regulation of Bcl-2 and up-regulation
of Bax. The p53-dependent negative response
element on Bcl-2 has the features of a
transcriptional silencer, mediating inhibition
of transcription in an orientation-dependent
manner. In a variety of tumors, p53 expression
is associated with apoptosis and with sensitivity
to DNA damaging agents (anticancer drugs and
ionizing radiations), by enhancing the transcription
of a gene that favours apoptosis
(Bax), at the same time blocking the transcription
of a gene that would protect cancer cells
from apoptosis (Bcl-2). Bcl-2 over-expression
is able to hinder p53-induced apoptosis, but
it is ineffective against p53-dependent growth
arrest. However, when Bcl-2 is expressed
together with the proto-oncogene c-myc, both