Download Farnesol-induced apoptosis in human lung carcinoma cells is

Farnesol-induced apoptosis in human lung carcinoma
cells is coupled to the endoplasmic reticulum stress
response.
Joo JH, Liao G, Collins JB, Grissom SF, Jetten AM.
Farnesol (FOH) and other isoprenoid alcohols induce apoptosis in various
carcinoma cells and inhibit tumorigenesis in several in vivo models.
However,
the mechanisms by which they mediate their effects are not yet fully
understood. In this study, we show that FOH is an effective inducer of
apoptosis in several lung carcinoma cells, including H460.
This induction is
associated with activation of several caspases and cleavage of
poly(ADP-ribose) polymerase (PARP).
To obtain insight into the mechanism
involved in FOH-induced apoptosis, we compared the gene expression profiles
of FOH-treated and control H460 cells by microarray analysis.
This analysis
revealed that many genes implicated in endoplasmic reticulum (ER) stress
signaling, including ATF3, DDIT3, HERPUD1, HSPA5, XBP1, PDIA4, and
PHLDA1, were highly up-regulated within 4 h of FOH treatment, suggesting
that FOH-induced apoptosis involves an ER stress response.
This was
supported by observations showing that treatment with FOH induces splicing of
XBP1 mRNA and phosphorylation of eIF2alpha.
FOH induces activation of
several mitogen-activated protein kinase (MAPK) pathways, including p38,
MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK, and
c-jun NH(2)-terminal kinase (JNK).
Inhibition of MEK1/2 by U0126 inhibited
the induction of ER stress response genes.
In addition, knockdown of the
MEK1/2 and JNK1/2 expression by short interfering RNA (siRNA) effectively
inhibited the cleavage of caspase-3 and PARP and apoptosis induced by FOH.
However, only MEK1/2 siRNAs inhibited the induction of ER stress-related
genes, XBP1 mRNA splicing, and eIF2alpha phosphorylation.
Our results
show that FOH-induced apoptosis is coupled to ER stress and that activation of
MEK1/2 is an early upstream event in the FOH-induced ER stress signaling
cascade. [Cancer Res 2007;67(16):7929-36].
Circulating insulin-like growth factor binding protein-1 and
the risk of pancreatic cancer.
Wolpin BM, Michaud DS, Giovannucci EL, Schernhammer ES, Stampfer MJ,
Manson JE, Cochrane BB, Rohan TE, Ma J, Pollak MN, Fuchs CS.
Department of Medical Oncology, Dana-Farber Cancer Institute.
Insulin-like growth factor (IGF)-I has growth-promoting effects on pancreatic
cancer cells, and elevated fasting serum insulin has been linked to pancreatic
cancer risk.
IGF binding protein-1 (IGFBP-1) is a downstream target of insulin
and inhibits IGF-I activity.
To investigate whether prediagnostic plasma levels
of IGFBP-1 are associated with pancreatic cancer risk, we did a prospective,
case-control study nested within the Health Professionals Follow-up Study, the
Nurses' Health Study, the Physicians' Health Study, and the Women's Health
Initiative.
We assayed circulating IGFBP-1 among 144 pancreatic cancer
cases that occurred >/=4 years after plasma collection and in 429 controls,
matched for date of birth, prospective cohort, smoking status, and fasting
status.
When compared with participants in the three highest quartiles of
plasma IGFBP-1, those in the lowest quartile experienced a relative risk (RR)
for pancreatic cancer of 2.07 [95% confidence intervals (95% CI), 1.26-3.39],
after adjusting for other risk factors, including circulating IGF-I, IGF binding
protein-3, and C-peptide.
Only participants in the lowest quartile of plasma
IGFBP-1 showed an elevated risk of pancreatic cancer.
The influence of low
plasma IGFBP-1 became progressively stronger with time; among cases
diagnosed >/=8 years after blood collection, the adjusted RR was 3.47 (95% CI,
1.48-8.14), comparing the bottom versus the top three quartiles.
The
influence of plasma IGFBP-1 was most marked among participants who never
smoked cigarettes (RR, 3.30; 95% CI, 1.48-7.35).
Among participants in four
U.S. prospective cohort studies, low plasma IGFBP-1 levels significantly
predicted an increased risk of pancreatic cancer. [Cancer Res
2007;67(16):7923-8].
Platelet-Derived Growth Factor Receptor Regulates
Myeloid and Monocytic Differentiation of HL-60 Cells.
Reiterer G, Yen A.
Department of Biomedical Sciences, Cornell University, Ithaca, New York.
Here, we show that the platelet-derived growth factor receptor (PDGFR)
regulates myeloid and monocytic differentiation of HL-60 myeloblastic
leukemia cells in response to retinoic acid (RA) and vitamin D3 (D3),
respectively.
Both RA and D3 decreased the expression of PDGFR-alpha
and PDGFR-beta throughout differentiation.
When cells were treated with the
PDGFR inhibitor AG1296 in addition to RA or D3, signs of terminal
differentiation such as inducible oxidative metabolism and cell substrate
adhesion were enhanced.
These changes were accompanied by an
increased extracellular signal-regulated kinase 1/2 activation.
AG1296 also
resulted in elevated expression of differentiation markers CD11b and CD66c
when administered with RA or D3.
the same pattern.
Interestingly, other markers did not follow
Cells receiving AG1296 in addition to RA or D3 showed
decreased G(1)-G(0) arrest and CD14, CD38, and CD89 expression.
We
thus provide evidence that certain sets of differentiation markers can be
enhanced, whereas others can be inhibited by the PDGFR pathway.
In
addition, we found calcium levels to be decreased by RA and D3 but increased
when AG1296 was given in addition to RA or D3, suggesting that calcium
levels decrease during myeloid or monocytic differentiation, and elevated
calcium levels can disturb the expression of certain differentiation markers.
[Cancer Res 2007;67(16):7765-71].
Estrogen Receptor {alpha} Inhibits p53-Mediated
Transcriptional Repression: Implications for the
Regulation of Apoptosis.
Sayeed A, Konduri SD, Liu W, Bansal S, Li F, Das GM.
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute,
Buffalo, New York.
Estrogen receptor alpha (ERalpha) and tumor suppressor protein p53 exert
opposing effects on cellular proliferation.
As a transcriptional regulator, p53 is
capable of activating or repressing various target genes.
We have previously
reported that ERalpha binds directly to p53, leading to down-regulation of
transcriptional activation by p53.
In addition to transcriptional activation,
transcriptional repression of a subset of target genes by p53 plays important
roles in diverse biological processes, such as apoptosis.
Here, we report that
ERalpha inhibits p53-mediated transcriptional repression.
Chromatin
immunoprecipitation assays reveal that ERalpha interacts in vivo with p53
bound to promoters of Survivin and multidrug resistance gene 1, both targets
for transcriptional repression by p53.
ERalpha binding to p53 leads to
inhibition of p53-mediated transcriptional regulation of these genes in human
cancer cells.
Transcriptional derepression of Survivin by ERalpha is
dependent on the p53-binding site on the Survivin promoter, consistent with
our observation that p53 is necessary for ERalpha to access the promoters.
Importantly, mutagenic conversion of this site to an activation element enabled
ERalpha to repress p53-mediated transcriptional activation.
Further, RNA
interference-mediated knockdown of ERalpha resulted in reduced Survivin
expression and enhanced the propensity of MCF-7 cells to undergo apoptosis
in response to staurosporine treatment, an effect that was blocked by
exogenous expression of Survivin.
These results unravel a novel mechanism
by which ERalpha opposes p53-mediated apoptosis in breast cancer cells.
The findings could have translational implications in developing new
therapeutic and prevention strategies against breast cancer. [Cancer Res
2007;67(16):7746-55].
Retinoblastoma: from the two-hit hypothesis to targeted
chemotherapy.
Macpherson D, Dyer MA.
Department of Embryology, Carnegie Institution, Baltimore, Maryland.
Studies on retinoblastoma have been at the heart of many of the landmark
discoveries in cancer genetics over the past 35 years.
However, these
advances in the laboratory have had little effect on the treatment of children
with retinoblastoma.
One of the reasons for this has been the lack of
preclinical models that recapitulated the genetic and histopathologic features of
human retinoblastoma.
In the past three years, a series of new animal
models of retinoblastoma has been developed and characterized from several
different laboratories using a variety of experimental approaches.
It is
encouraging that there is broad agreement about the consequences of
inactivation of the Rb family in retinal development from these studies.
More
importantly, these new mouse models of retinoblastoma have contributed to
clinical trials and novel therapeutic approaches for treating this debilitating
childhood cancer.
[Cancer Res 2007;67(16):7547-50].
Early developmental pathology due to cytochrome c
oxidase deficiency is revealed by a new zebrafish model.
Baden KN, Murray J, Capaldi RA, Guillemin K.
Biology, Institute of Molecular Biology, University of Oregon, Eugene, OR
97403.
Deficiency of cytochrome c oxidase (COX) is associated with significant
pathology in humans.
However, the consequences for organogenesis and
early development are not well understood. We have investigated these
issues using a zebrafish model.
COX deficiency was induced using
morpholinos to reduce expression of CoxVa, a structural subunit, and Surf1, an
assembly factor, both of which impaired COX assembly.
Reduction of COX
activity to 50% resulted in developmental defects in endodermal tissue, cardiac
function, and swimming behavior.
underlying mechanisms.
Cellular investigations revealed different
Apoptosis was dramatically increased in the
hindbrain and neural tube and secondary motor neurons were absent or
abnormal, explaining the motility defect.
In contrast, the heart lacked
apoptotic cells but showed increasingly poor performance over time, consistent
with energy deficiency. The zebrafish model has revealed tissue-specific
responses to COX deficiency and holds promise for discovery of new therapies
to treat mitochondrial diseases in humans.
Induction of endogenous UCP3 suppresses mitochondrial
oxidant emission during fatty-acid supported respiration.
Anderson EJ, Yamazaki H, Neufer PD.
Department of Exercise and Sport Science & Department of Physiology, East
Carolina University, Greenville, NC 27858.
Uncoupling protein 3 (UCP3) expression increases dramatically in skeletal
muscle under metabolic states associated with elevated lipid metabolism, yet
the function of UCP3 in a physiological context remains controversial.
Here,
in situ mitochondrial H{sub}2O{sub}2 emission and respiration were measured
in permeabilized fiber bundles prepared from both rat and mouse (wild-type)
gastrocnemius muscle after a single bout of exercise plus 18h recovery (Ex/R)
that induced a ~2- to 4-fold increase in UCP3 protein.
Elevated uncoupling
activity (i.e., GDP inhibitable) was evident in Ex/R fibers only upon addition of
palmitate (known activator of UCP3) or under substrate conditions eliciting
substantial rates of H{sub}2O{sub}2 production (i.e., respiration supported by
succinate or palmitoyl-L-carnitine/malate, but not pyruvate/malate), indicative
of UCP3 activation by endogenous ROS.
In mice completely lacking UCP3
(ucp3 -/-), Ex/R failed to induce uncoupling activity.
Surprisingly, when UCP3
activity was inhibited by GDP (rats) or in the absence of UCP3 (ucp3 -/-),
H{sub}2O{sub}2 emission was significantly (P<0.05) higher in Ex/R versus
non-exercised control fibers.
Collectively, these findings demonstrate that the
oxidant emitting potential of mitochondria is increased in skeletal muscle during
recovery from exercise, possibly as a consequence of prolonged reliance on
lipid metabolism and/or altered mitochondrial biochemistry/morphology, and
that induction of UCP3 in vivo mediates an increase in uncoupling activity that
restores mitochondrial H{sub}2O{sub}2 emission to non-exercised, control
levels.
Lactogens promote beta cell survival through JAK2/STAT5
activation and BCL-XL upregulation.
Fujinaka Y, Takane K, Yamashita H, Vasavada RC.
Medicine, University of Pittsburgh, Pittsburgh, PA 15261.
One of the goals in the treatment for diabetes is to enhance pancreatic beta
cell function, proliferation, and survival.
This study explores the role of
lactogenic hormones, prolactin (PRL) and placental lactogen (PL), in beta cell
survival.
We have previously shown that transgenic mice expressing mouse
placental lactogen-1 (mPL1) in beta cells under the rat insulin II promoter (RIP)
are resistant to the diabetogenic and cytotoxic effects of streptozotocin (STZ) in
vivo.
The current study demonstrates that lactogens protect rat insulinoma
(INS-1) cells and primary mouse beta cells against two distinct beta cell death
inducers, STZ and dexamethasone (DEX), in vitro.
Further, we identify the
mechanism through which lactogens protect beta cells against DEX-induced
death.
The signaling pathway mediating this protective effect is the
janus-activated-kinase-2/ signal transducer and activator of transcription-5
(JAK2/STAT5) pathway.
This is demonstrated in INS-1 cells and primary
mouse beta cells using three separate approaches, pharmacological inhibitors,
JAK2-specific siRNAs and a dominant-negative STAT5 mutant.
Furthermore,
lactogens specifically and significantly increase the anti-apoptotic protein
Bcl-XL in insulinoma cells and mouse islets.
Bcl-XL-specific siRNA
significantly inhibits lactogen-mediated protection against DEX-induced beta
cell death.
We believe this is the first direct demonstration of lactogens
mediating their protective effect through the JAK2/STAT5 pathway in the beta
cell, and through Bcl-XL in any cell type.
A honey bee odorant receptor for the queen substance
9-oxo-2-decenoic acid.
Wanner KW, Nichols AS, Walden KK, Brockmann A, Luetje CW, Robertson
HM.
Department of Entomology, University of Illinois at Urbana–Champaign,
Urbana, IL 61801.
By using a functional genomics approach, we have identified a honey bee [Apis
mellifera (Am)] odorant receptor (Or) for the queen substance
9-oxo-2-decenoic acid (9-ODA). Honey bees live in large eusocial colonies in
which a single queen is responsible for reproduction, several thousand sterile
female worker bees complete a myriad of tasks to maintain the colony, and
several hundred male drones exist only to mate.
The "queen substance" [also
termed the queen retinue pheromone (QRP)] is an eight-component
pheromone that maintains the queen's dominance in the colony. The main
component, 9-ODA, acts as a releaser pheromone by attracting workers to the
queen and as a primer pheromone by physiologically inhibiting worker ovary
development; it also acts as a sex pheromone, attracting drones during mating
flights.
However, the extent to which social and sexual chemical messages
are shared remains unresolved.
By using a custom chemosensory-specific
microarray and qPCR, we identified four candidate sex pheromone Ors
(AmOr10, -11, -18, and -170) from the honey bee genome based on their
biased expression in drone antennae.
We assayed the pheromone
responsiveness of these receptors by using Xenopus oocytes and
electrophysiology. AmOr11 responded specifically to 9-ODA (EC50 = 280 +/31 nM) and not to any of the other seven QRP components, other social
pheromones, or floral odors.
We did not observe any responses of the other
three Ors to any of the eight QRP pheromone components, suggesting 9-ODA
is the only QRP component that also acts as a long-distance sex pheromone.
Apoptotic cells protect mice from autoimmune
inflammation by the induction of regulatory B cells.
Gray M, Miles K, Salter D, Gray D, Savill J.
*Medical Research Council Centre for Inflammation Research, The Queen's
Medical Research Institute, University of Edinburgh, 47 Little France Crescent,
Edinburgh EH16 4TJ, United Kingdom.
The maintenance of immune tolerance to apoptotic cells (AC) within an
inflammatory milieu is vital to prevent autoimmunity.
To investigate this, we
administered syngeneic AC i.v. into mice carrying a cohort of ovalbumin
(OVA)-specific transgenic T cells (DO11.10) along with OVA peptide and
complete Freund's adjuvant, observing a dramatic increase in OVA-specific
IL-10 secretion.
Activated splenic B cells responded directly to AC, increasing
secretion of IL-10, and this programming by AC was key to inducing T
cell-derived IL-10.
We went on to ask whether AC are able to modulate the
course of autoimmune-mediated, chronic inflammation.
AC given up to 1
month before the clinical onset of collagen-induced arthritis protected mice
from severe joint inflammation and bone destruction.
Antigen-specific CD4(+)
T cells again secreted significantly more IL-10, associated with a reduced titer
of pathogenic anti-collagen II antibodies.
the beneficial effects of AC.
Inhibition of IL-10 in vivo reversed
Passive transfer of B cells from AC-treated mice
provided significant protection from arthritis.
These data demonstrate that AC
exert a profound influence on an adaptive immune response through the
generation of CD19(+) regulatory B cells, which in turn are able to influence the
cytokine profile of antigen-specific effector T cells.
進階科技英文寫作測驗
1. estrogen receptor alpha 或 the estrogen receptor alpha
2. tumor suppressor protein p53 或 the tumor suppressor protein p53
3. They exert opposing effect on cellular proliferation. 或 They exert opposing effects on
cellular proliferation. 或 They exert opposing effects on the cellular proliferation.
4. As a transcriptional regulator, p53 is ... 或 As transcriptional regulator, p53 is ...
5. P53 is capable of activating various target genes. 或 P53 is capable of the activating
various target genes. 或 P53 is capable of the activating of various target genes. P53 is
capable of activation various target genes. P53 is capable of activation of various target
genes. 或 P53 is capable of the activation of various target genes.
6. P53 is capable of activating or repressing various target genes. 或 P53 is capable of
activating or repressing the various target genes. 或 P53 is able to activate or repress
various target genes.
7. We have previously reported that ... 或 We previously reported that ... 或 We have
previous reported that ... 或 We have a previous report that ...
8. ERalpha binds directly to p53. 或 ERalpha is bound directly to p53.
9. ERalpha binds directly to p53, leading to ... 或 ERalpha binds directly to p53, leads to ...
10. ERalpha binds directly to p53, leading to down-regulation of transcriptional activation by
p53. 或 ERalpha binds directly to p53, leading to the down-regulation of the
transcriptional activation of p53.
11. In addition to transcriptional activation, transcriptional repression plays important role in
diverse biological process. 或 In addition to transcriptional activation, transcriptional
repression plays important roles in diverse biological processes.
12. Transcriptional repression of a subset of target genes by p53 plays ... 或 Transcriptional
repression by a subset of target genes of p53 play ...
13. ... in diverse biological processes, such as apoptosis. 或 ... in diverse biological processes
such as the apoptosis.
14. Here, we report that ... 或 Here, we reported that ...
15. Here, we report that ERalpha inhibited p53-mediating transcriptional repression. 或 Here,
we report that ERalpha inhibits p53-mediated transcriptional repression.
16. Chromatin immunoprecipitation assays reveal that ... 或 Chromatin immunoprecipitation
assay revealed that ...
17. ... assays reveal that ERalpha interacts in vivo with p53 bound to promoters of Survivin.
或 ... assays reveal that ERalpha interacted in vivo with p53 binding to promoters of
Survivin.
18. ERalpha interacts in vivo with p53 bound to promoters of Survivin and multidrug
resistance gene 1. 或 ERalpha interacts in vivo with p53 bound to promoters of Survivin
and of multidrug resistance gene 1.
19. ... Survivin and multidrug resistance gene 1, both targets for transcriptional repression by
p53. 或 ... Survivin and multidrug resistance gene 1, both being targets for transcriptional
repression by p53.
20. ERalpha binding to p53 leads to inhibition of p53-mediated transcriptional regulation of
these genes in human cancer cells. 或 ERalpha binds to p53 leading to inhibition of
p53-mediated transcriptional regulation of these gene in human cancer cell.