|
Exp Hematol. 2007 Nov 17 [Epub
ahead of print]
Links
Bcl2 enhances induced hematopoietic
differentiation of murine embryonic stem cells.
Wang
YY, Deng
X, Xu L, Gao F, Flagg T, May
WS.
University of Florida
Shands Cancer
Center and Department of Medicine,
University of Florida,
Gainesville, Fla.,
USA.
Bcl2 is a potent antiapoptotic gene that can increase resistance of
adult bone marrow hematopoietic progenitor
cells to lethal irradiation, and thereby preserve their ability to
differentiate. However, the effect of Bcl2 on murine
embryonic stem (ES) cells induced to undergo hematopoietic
differentiation in the absence of a toxic stress is not known. To test
this, murine CCE-ES cells that can be induced
to undergo hematopoietic differentiation in a
two-step process that results in upregulation
of Bcl2 were used. Upregulation of Bcl2
precedes formation of hematopoietic embryoid bodies (EB) and their further
differentiation into hematopoietic
colony-forming units, when plated as single cells in methylcellulose. ES
cells stably expressing a Bcl2 siRNA plasmid to
"knock-down" endogenous expression or cells expressing
wild-type (WT) Bcl2 or phosphomimetic Bcl2
mutants were examined. ES cells expressing the Bcl2 siRNA
or those expressing a dominant-negative, nonphosphorylatable
Bcl2 display a strikingly reduced capacity to form hematopoietic
EBs and colony-forming units compared to cells
expressing WT or phosphomimetic Bcl2 that
demonstrate an increased capacity. Bcl2's effect on induced-hematopoietic differentiation of ES cells does not
result from either decreased apoptosis or a reduced number of cells.
Rather, Bcl2-enhances hematopoietic
differentiation of ES cells by upregulating
p27, which results in retardation of the cell cycle at G(1)/G(0).
Thus siRNA silencing of p27 reverts Bcl2's
enhancement phenotype in a manner similar to that of Bcl2
"silencing" or expression of a nonphosphorylable
Bcl2. In addition to Bcl2's well-described antiapoptotic
and cell-cycle retardant effect on somatic cells, Bcl2 may also function
to enhance induced hematopoietic cell
differentiation of murine ES cells. These
findings may have potential relevance for expanding hematopoietic
stem/progenitor cell numbers from an ES cell source for stem cell
transplantation applications.
PMID: 18023519 [PubMed - as supplied by publisher]
Bcl2 suppresses DNA repair by enhancing
c-Myc transcriptional activity.
Jin Z, May WS, Gao
F, Flagg
T, Deng X.
Department of Medicine, University of Florida
Shands Cancer
Center, Gainesville,
FL 32610-0232.
Bcl2 and c-Myc are two major oncogenic proteins that can functionally promote DNA
damage, genetic instability and tumorigenesis.
However, the mechanism(s) remains unclear. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is
the most potent carcinogen contained in cigarette smoke that induces
cellular DNA damage. Here we found that Bcl2 potently suppresses the
repair of NNK-induced abasic sites of DNA
lesions in association with increased c-Myc
transcriptional activity. Bcl2's BH4 domain (aa
6-31) was found to bind directly to c-Myc's
MBII domain (aa 106-143) and this interaction
is required for Bcl2 to enhance c-Myc
transcriptional activity and inhibit DNA repair. In addition to
mitochondria, Bcl2 is also expressed in the nucleus where it co-localizes
with c-Myc. Expression of nuclear-targeted Bcl2
enhances c-Myc transcriptional activity with
suppression of DNA repair but fails to prolong cell survival. Depletion
of c-Myc expression from cells overexpressing Bcl2 significantly accelerates the
repair of NNK-induced DNA damage, indicating that c-Myc
may be essential for Bcl2's effect on DNA repair. It is known that APE1
plays a crucial role in the repair of abasic
sites of DNA lesions. Since overexpression of
Bcl2 results in up-regulation of c-Myc and
down-regulation of APE1, this suggests that APE1 may function as the
downstream target of Bcl2/c-Myc in the DNA repair machinery. Thus, Bcl2,
in addition to its survival function, may also suppress DNA repair in a
novel mechanism involving c-Myc and APE1, which
may lead to an accumulation of DNA damage in living cells, genetic
instability and tumorigenesis.
PMID: 16554306 [PubMed - as supplied by
publisher]
Expression of bcl-2 and
p53 in Merkel cell carcinoma. An immunohistochemical
study.
¡P
Kennedy MM,
Blessing K,
King G, Kerr KM.
Department of Pathology, Aberdeen University, Foresterhill, Scotland.
Bcl-2 is a protooncogene
thought to play a role in oncogenesis by
inhibiting programmed cell death. It may interact with p53, a
tumor-suppressor gene which induces apoptosis in certain circumstances.
We have studied these gene products by immunohistochemistry
in 15 cases of Merkel cell carcinoma, a tumor characterised
by prominent apoptosis. Five cases showed moderate/strong staining for
p53, with moderate/strong bcl-2 staining in 10 patients. In seven cases
abundance of p53 and bcl-2 expression was mutually exclusive. Two
patients died within 1 year of diagnosis and six had nodal recurrences.
Gene expression and survival appear unrelated. The role of Bcl-2 and p53
in tumorigenesis is complicated and may be
inter-related with other genes known to be involved in programmed cell
death.
PMID: 8806961 [PubMed -
indexed for MEDLINE]
Leptin decreases apoptosis and alters BCL-2 : Bax ratio in clonal rodent pancreatic beta-cells.
¡P
Brown JE,
Dunmore SJ.
Diabetes and Metabolic Disorders Research
Group, RIHS, University of Wolverhampton, Wulfruna St, Wolverhampton, WV1 1SB, UK.
AIMS/HYPOTHESIS: The adipocyte
derived peptide hormone leptin is known to
regulate apoptosis and cell viability in several cells and tissues, as
well as having several pancreatic islet beta-cell specific effects such
as inhibition of glucose-stimulated insulin secretion. This study
investigated the effects of leptin upon
apoptosis induced by serum depletion and on expression of the apoptotic
regulators B-cell leukaemia 2 gene product (BCL-2) and BCL2-associated X protein (Bax) in the glucose-responsive BRIN-BD11 beta-cell
line. METHODS: BRIN-BD11 cells were cultured in RPMI 1640 and
subsequently serum depleted +/- leptin (10 and
50 ng/mL) for 24 h. Cell viability and
apoptosis were measured using a modified MTS assay and TUNEL/YO-PRO-1
assays, respectively. BCL-2 and Bax expression
were measured by real-time PCR and Western blotting. RESULTS: Leptin caused a reduction in serum-depleted
apoptosis, although it failed to have any effect on the overall cell
viability, causing a 68% shift from apoptosis to necrosis. Leptin significantly increased the level of BCL-2
mRNA expression (150% compared to serum depletion alone), without
altering Bax mRNA expression. At the protein
level, leptin increased BCL-2 and decreased Bax, altering the BCL-2 : Bax ratio. CONCLUSIONS: We conclude that leptin reduces apoptosis in beta-cells at
physiological concentrations, possibly via its ability to up-regulate
BCL-2 and Bax expression. Copyright (c) 2007
John Wiley & Sons, Ltd.
PMID: 17318810 [PubMed -
as supplied by publisher
Cell survival, cell
death and cell cycle pathways are interconnected: Implications for cancer
therapy.
¡P
Maddika
S, Ande
SR, Panigrahi
S, Paranjothy
T, Weglarczyk
K, Zuse
A, Eshraghi
M, Manda
KD, Wiechec
E, Los M.
Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba,
Winnipeg, Canada; Department of Biochemistry and Medical Genetics,
University of Manitoba, Winnipeg, Canada.
The partial cross-utilization of molecules and
pathways involved in opposing processes like cell survival, proliferation
and cell death, assures that mutations within one signaling cascade will
also affect the other opposite process at least to some extent, thus
contributing to homeostatic regulatory circuits. This review highlights
some of the connections between opposite-acting pathways. Thus, we
discuss the role of cyclins in the apoptotic
process, and in the regulation of cell proliferation. CDKs
and their inhibitors like the INK4-family (p16(Ink4a),
p15(Ink4b), p18(Ink4c), p19(Ink4d)), and the Cip1/Waf1/Kip1-2-family
(p21(Cip1/Waf1), p27(Kip1), p57(Kip2)) are shown both in the context of
proliferation regulators and as contributors to the apoptotic machinery.
Bcl2-family members (i.e. Bcl2, Bcl-X(L) Mcl-1(L); Bax, Bok/Mtd, Bak, and Bcl-X(S); Bad, Bid, Bim(EL),
Bmf, Mcl-1(S)) are highlighted both for their
apoptosis-regulating capacity and also for their effect on the cell cycle
progression. The PI3-K/Akt cell survival pathway is shown as regulator of
cell metabolism and cell survival, but examples are also provided where
aberrant activity of the pathway may contribute to the induction of
apoptosis. Myc/Mad/Max proteins are shown both
as a powerful S-phase driving complex and as apoptosis-sensitizers. We
also discuss multifunctional proteins like p53 and Rb
(RBL1/p107, RBL2/p130) both in the context of G(1)-S
transition and as apoptotic triggers. Finally, we reflect on novel
therapeutic approaches that would involve redirecting over-active
survival and proliferation pathways towards induction of apoptosis in
cancer cells.
PMID: 17303468 [PubMed -
as supplied by publisher
|
Cancer
B-cell lymphoma
Non-Hodgkin
Lymphomas
Oral cancer
Stem cell
