| Current
Molecular Medicine
ISSN: 1566-5240
Current Molecular Medicine
Volume 8, Number 6, September 2008
Contents
c-Myc: Linking Transformation and Genomic Instability
Pp. 446-458
Edward V. Prochownik
[Abstract] [Purchase
Article]
Roles of NHERF1/EBP50 in Cancer Pp.
459-468
Maria-Magdalena Georgescu, Fabiana C. Morales,
Jennifer R. Molina and Yuho Hayashi
[Abstract] [Purchase
Article]
HGF/MET Signaling in Ovarian Cancer Pp.
469-480
Hong Yan Zhou, Yuen Lam Pon and Alice
S.T. Wong
[Abstract] [Purchase
Article]
Erythropoietin in Cancer: An Update Pp. 481-491
József Tóvári, Robert Pirker, József
Tímár, Gyula Ostoros, Gábor Kovács
and Balázs Döme
[Abstract] [Purchase
Article]
Metastasis-Inducing S100A4 Protein: Implication in Non-Malignant
Human Pathologies Pp. 492-496
Mariam Grigorian, Noona Ambartsumian and
Eugene Lukanidin
[Abstract] [Purchase
Article]
Pneumolysin: A Double-Edged Sword During the Host-Pathogen
Interaction Pp. 497-509
Helen M. Marriott, Timothy J. Mitchell and
David H. Dockrell
[Abstract] [Full
text article]
Chagas Heart Disease Pathogenesis: One
Mechanism or Many? Pp. 510-518
Kevin M. Bonney and David M. Engman
[Abstract] [Purchase
Article]
Genes, Environment, and Interactions
in Prevention of Type 2 Diabetes: A Focus on Physical Activity
and Lifestyle Changes Pp. 519-532
Lu Qi, Frank B. Hu and Gang Hu
[Abstract] [Purchase
Article]
Cardiovascular Disease in Patients with
Diabetic Nephropathy Pp. 533-543
Yoshimasa Aso
[Abstract] [Purchase
Article]
Multi-System Disorder Syndromes Associated with Cystinuria
Type I Pp. 544-550
Kevin Martens, Jaak Jaeken, Gert Matthijs
and John W.M. Creemers
[Abstract] [Purchase
Article]
Genetic Susceptibility to Autoimmune Disorders: Clues from
Gene Association and Gene Expression Studies Pp.
551-561
Ilse Gutierrez-Roelens and Bernard
R. Lauwerys
[Abstract] [Purchase
Article]
Peroxisome Proliferator-Activated Receptor-γ
(PPAR-γ)
Ligands: Novel Pharmacological Agents in the Treatment of
Ischemia Reperfusion Injury Pp. 562-579
Costas Giaginis, Gerasimos Tsourouflis and
Stamatios Theocharis
[Abstract] [Purchase
Article]
The Many Faces of Amyloid β
in Alzheimer's Disease Pp. 580-584
Peter K. Chiang, Michael A. Lam and
Yuan Luo
[Abstract] [Purchase
Article]
Targeting Eosinophils in Asthma Pp. 585-590
Paul S. Foster, Helene F. Rosenberg, Kelly
L. Asquith and Rakesh K. Kumar
[Abstract] [Purchase
Article]
Abstracts
[Back to top]
[Purchase
Article]
c-Myc: Linking Transformation and Genomic
Instability
Edward V. Prochownik
CMYC has long been known to be among the
most frequently de-regulated oncogenes in human cancer. Only
recently, however has a clear understanding begun to emerge
of how it promotes transformation. Through its role as a transcription
factor, c-Myc alters the expression of hundreds of target
genes, many of which are themselves oncogenes or tumor suppressors.
The deregulation of c-Myc is both necessary and sufficient
for the “acute” type of rapid in vitro
transformation that occurs in certain established rodent cell
lines. Transformation of primary rodent cells in vitro
is also rapid but requires the contribution of at least one
additional cooperating oncogene such as Ras. In contrast,
the “chronic” form of in vivo transformation
by c-Myc is a rare event that requires the acquisition of
multiple mutations in other genes affecting cell cycle, senescence,
and apoptosis. By greatly accelerating the intrinsic mutation
rate at several levels, c-Myc increases the like-lihood that
these additional mutational “hits” will occur.
Among the types of genomic instability mediated by c-Myc are
single nucleotide substitutions and double-stranded breaks
arising via the induction of reactive oxygen species,
gene amplification and the generation of extrachromosomal
elements, and numerical chromosomal defects resulting from
aberrant DNA synthesis and defects in the mitotic spindle
checkpoint. These non-mutually exclusive activities ensure
a constant and varied source of genotoxic insults and suggest
that c-Myc over-expression imposes a "mutator phenotpye".
This may be an early and necessary requirement for the initial
steps in chronic transformation as well as for subsequent
evolutionary changes that produce important tumor behaviors
such as invasiveness, metastasis, and acquisition of chemotherapy
resistance.
[Back to top]
[Purchase
Article]
Roles of NHERF1/EBP50 in Cancer
Maria-Magdalena Georgescu, Fabiana C. Morales,
Jennifer R. Molina and Yuho Hayashi
This review summarizes the emerging roles of NHERF1/EBP50
adaptor protein in tumorigenesis. NHERF1/EBP50 (Na+/H+
exchanger regulating factor 1; ezrin-radixin-moesin
(ERM) binding phosphoprotein of 50
kDa) is a PDZ domain-containing protein with physiological
localization at the plasma membrane. We discuss in this review
the functions of NHERF1/EBP50 as a linker between membrane
proteins and the cytoskeleton network, as well as its involvement
in different types of cancer, such as breast and liver cancers.
Recent evidence obtained from our laboratory and from other
groups shows that NHERF1/EBP50 is an important player in cancer
progression. It appears that, depending on its subcellular
distribution, NHERF1/EBP50 may behave either as a tumor suppressor,
when it is localized at the plasma membrane, or as an oncogenic
protein, when it is shifted to the cytoplasm. We provide here
an overview of the mechanisms by which this adaptor protein
controls cell transformation, and propose a model suggesting
a dual role of NHERF1/EBP50 in cancer.
[Back to top]
[Purchase
Article]
HGF/MET Signaling in Ovarian Cancer
Hong Yan Zhou, Yuen Lam Pon and Alice
S.T. Wong
Ovarian cancer is the leading cause of death from
gynecological cancers in North America and Europe. Despite
its clinical significance, the factors that regulate the development
and progression of ovarian cancer are among the least understood
of all major human malignancies. A growth factor with pleiotropic
effects, which has attracted increasing attention in recent
years, is the hepatocyte growth factor (HGF) and its receptor
MET. While deregulated HGF/MET signaling is observed in many
tumors, the consequences of MET activation are complex and
context dependent. Recent observations have demonstrated a
cross-talk of other signaling pathways with MET signaling.
This review summarizes the key findings and recent advances
in our understanding of HGF and MET in the transformation
and progression of ovarian cancer. We will begin with a brief
discussion on the role of HGF and MET in the physiology of
normal ovarian surface epithelium (OSE) and ovarian cancer
development. In particular, the coexpression of HGF and MET
in OSE of women with hereditary ovarian cancer syndromes emphasizes
their importance in neoplastic transformation of OSE. The
involvement of HGF in other aspects of tumor progression,
such as invasion and metastasis, and novel downstream target
genes activated by HGF is summarized next. The therapeutic
potential of HGF to treat ovarian cancer and to improve response
to conventional chemotherapy is also described. Finally, the
most recent progress in drug development and future areas
of research in terms of their potential clinical implications
are discussed.
[Back to top]
[Purchase Article]
Erythropoietin in Cancer: An Update
József Tóvári, Robert Pirker, József
Tímár, Gyula Ostoros, Gábor Kovács
and Balázs Döme
Erythropoietin (EPO) has long been recognized as
the major hematopoietic cytokine regulating normal erythropoiesis.
Moreover, there is a growing interest in the non-erythropoietic,
tissue-protective effects of EPO. Because of its potential
to correct anemia, EPO has been increasingly prescribed to
cancer patients. However, although recombinant human Epo (rHuEPO)
significantly reduces the risk for red blood cell transfusions
in cancer patients, recent clinical studies have reported
decreased survival and disease control following rHuEPO treatment
in patients with different cancer types. The issue of EPOR
expression in tumor cells is critical in this respect. The
expression of EPOR in tumor cells raises the possibility that
exogenous rHuEPO may directly influence tumor growth or sensitivity
to chemo-radiation therapy. In addition, EPOR expression in
endothelial cells suggests what potential effects EPO may
have on tumor capillaries, such as the stimulation of angiogenesis.
However, as experimental studies reveal, the overall direct
effect of EPO-EPOR signaling on cancer progression and therapy
is not a straightforward one. The current paper provides an
update on the biology of EPO, and discusses its utility in
the treatment of cancer patients.
[Back to top]
[Purchase
Article]
Metastasis-Inducing S100A4 Protein: Implication in Non-Malignant
Human Pathologies
Mariam Grigorian, Noona Ambartsumian and
Eugene Lukanidin
The role of S100A4 in tumor progression and metastasis
is well documented in numerous research articles and summarized
in several reviews [1-3]. Currently S100A4 is categorized
as an essential metastasis-promoting factor whose production
and secretion from “activated” stromal cells (fibroblasts,
immunocytes and vascular cells) is initiated and stimulated
by signals derived in tumor cells (cytokines, growth factors
and others).
However recent data gained from experimental and clinical
studies significantly extend our knowledge on S100A4. Implications
of S100A4 in various non-malignant pathological conditions
have been demonstrated by number of research groups. In the
mini-review we attempted to highlight the role of S100A4 in
other than cancer important human pathologies, such as autoimmune
inflammation (RA) and disorders in cardio-vascular, nervous
and pulmonary systems.
We suggest that diverse human diseases might have common molecular
components and pathway(s). Possibly, inflammatory machinery
and S100A4 as its intrinsic constituent could contribute to
the pathogenesis of various disorders. Therefore, we presume
that facts on S100A4 performance could be attractive for broad
range of researchers and clinicians.
[Back to top]
[Full
text article]
Pneumolysin: A Double-Edged Sword During the Host-Pathogen
Interaction
Helen M. Marriott, Timothy J. Mitchell and
David H. Dockrell
The cholesterol-dependent cytolysins are pore-forming
toxins. Pneumolysin is the cytolysin produced by Streptococcus
pneumoniae and is a key virulence factor. The protein
contains 471 amino acids and four structural domains. Binding
to cholesterol is followed by oligomerization and membrane
pore formation. Pneumolysin also activates the classical pathway
of complement. Mutational analysis of the toxin and knowledge
of sequence variation in outbreak strains suggests that additional
activities of biologic importance exist. Pneumolysin activates
a large number of genes, some by epigenetic modification,
in eukaryotic cells and multiple signal transduction pathways.
Cytolytic effects contribute to lung injury and neuronal damage
while pro-inflammatory effects compound tissue damage. Nevertheless
pneumolysin is a focal point of the immune response to pneumococci.
Toll-like receptor 4-mediated recognition, osmosensing and
T-cell responses to pneumolysin have been identified. In some
animal models mutants that lack pneumolysin are associated
with impaired bacterial clearance. Pneumolysin, which itself
may induce apoptosis in neurones and other cells can activate
host-mediated apoptosis in macrophages enhancing clearance.
Disease pathogenesis, which has traditionally focused on the
harmful effects of the toxin, increasingly recognises that
a precarious balance between limited host responses to pneumolysin
and either excessive immune responses or toxin-mediated subversion
of host immunity exists.
[Back to top]
[Purchase Article]
Chagas Heart Disease Pathogenesis: One Mechanism or Many?
Kevin M. Bonney and David M. Engman
Chagas heart disease (CHD), caused by the protozoan parasite
Trypanosoma cruzi, is the leading cause of infectious
myocarditis in the world. The etiology of CHD is unclear and
multiple mechanisms have been proposed to explain the pathogenesis
of the disease. This review describes the proposed mechanisms
of CHD pathogenesis and evaluates the historical significance
and evidence supporting each. Although the majority of CHD-related
pathologies are currently attributed to parasite persistence
in the myocardium and autoimmunity, there is strong evidence
that CHD develops as a result of additive and even synergistic
effects of several distinct mechanisms rather than one factor.
[Back to top]
[Purchase Article]
Genes, Environment, and Interactions in Prevention of Type
2 Diabetes: A Focus on Physical Activity and Lifestyle Changes
Lu Qi, Frank B. Hu and Gang Hu
Type 2 diabetes is one of the fastest growing public
health problems worldwide. Both environmental (e.g. physical
activity, obesity, and diet) and genetic factors are involved
in the development of type 2 diabetes. The associations between
physical activity and diabetes risk have been assessed by
a number of prospective studies and clinical trials. The results
from these studies consistently indicate that the regular
physical activity during occupation, commuting, leisure time
or daily life reduces the risk of type 2 diabetes by 15-60%;
and lifestyle intervention, including counselling for physical
activity, nutrition, and body weight, can reduce the risk
of type 2 diabetes by 40-60% among adults with impaired glucose
tolerance and by about 20% among general individuals.
In the past decade, studies using traditional linkage analysis
and candidate-gene association approach have found dozens
of genes harboring common variants that were related to the
common-form type 2 diabetes. However, most reported associations
are lack of reproducibility, except TCF7L2, PPARG, CAPN10,
and KCNJ11. Since 2007, seven genome-wide association
(GWA) studies emerged to generate a list of new diabetes genes.
The genetic effects are largely of moderate size. These findings
provide novel insight into the diabetes etiology and pave
new avenue for predicting the disease risk using genetic information.
In addition, data especially those from intervention trials
display preliminary but promising evidence that the genetic
variants might interact with physical activity in predisposing
to type 2 diabetes. The gene-environment interactions merit
extensive exploration in large, prospective studies.
[Back to top]
[Purchase
Article]
Cardiovascular Disease in Patients with Diabetic Nephropathy
Yoshimasa Aso
Diabetic nephropathy, which represents a major form
of chronic kidney disease (CKD), is a leading cause of end-stage
renal disease worldwide, and is also a risk factor for cardiovascular
disease (CVD). Patients with diabetes and CKD have poorer
outcomes after myocardial infarction. The underlying pathogenic
mechanism that links diabetic nephropathy to a high risk of
CVD remains unclear. In addition to traditional risk factors,
including hypertension, hyperglycemia, and dyslipidemia, identification
of novel modifiable risk factors is important in preventing
CVD in people with diabetes. Inflammation/oxidative stress
are known to be associated with an increased risk for CVD
in patients with diabetic nephropathy. Moreover, homocysteine,
advanced glycation end products, asymmetric dimethylarginine,
and anemia may play a role in the development and progression
of atherosclerosis in patients with diabetic nephropathy.
This review summarizes the epidemiologic evidence, molecular
mechanisms responsible for the increased risk for CVD in patients
with diabetic nephropathy, and therapeutic intervention for
diabetic nephropathy as evidenced by large-scale clinical
trials.
[Back to top]
[Purchase Article]
Multi-System Disorder Syndromes Associated with Cystinuria
Type I
Kevin Martens, Jaak Jaeken, Gert Matthijs
and John W.M. Creemers
Cystinuria type I is an autosomal recessive disorder
with an exclusively renal phenotype caused by inactivating
mutations in SLC3A1. Recently 3 similar but distinct
syndromes associated with cystinuria type I have been described:
2p21 deletion syndrome, Hypotonia-Cystinuria Syndrome (HCS)
and atypical HCS. Genetic analysis indicated that these are
recessive contiguous gene deletion syndromes which differ
in the number of genes affected. Patients with HCS are missing
both alleles of SLC3A1 and PREPL. In atypical
HCS an additional gene (C2orf34) is deleted, and
finally, in the 2p21 deletion syndrome the open reading frame
of PPM1B is also disrupted. With the exception of
SLC3A1, the gene products have not been fully characterized.
The severity of the different syndromes reflects the number
of genes which are deleted. HCS, a relatively mild syndrome,
is characterised by cystinuria type I, generalised hypotonia
at birth, growth retardation and minor facial dysmorphic features.
On the other end of the spectrum is the 2p21 deletion syndrome,
a severe syndrome with a number of additional features including
a moderate to severe psychomotor retardation and a decrease
in activity of the respiratory chain complexes I, III, IV
and V. Finally, atypical HCS displays an intermediate phenotype
comparable with classical HCS but associated with mild to
moderate mental retardation and a decrease in activity of
only the respiratory chain complex IV.
This review will focus on the phenotypic similarities and
differences observed in these syndromes. Furthermore, we speculate
on the function of the gene products, based on the available
data.
[Back to top]
[Purchase
Article]
Genetic Susceptibility to Autoimmune Disorders: Clues from
Gene Association and Gene Expression Studies
Ilse Gutierrez-Roelens and Bernard
R. Lauwerys
Susceptibility to autoimmune disorders results from the
interaction of multiple genetic factors that regulate the
threshold of autoreactivity. Genome-wide microsatellite screens
and large-scale single nucleotide polymorphism (SNP) association
studies have identified chromosomal loci that are associated
with specific disorders including systemic lupus erythematosus,
rheumatoid arthritis, juvenile arthritis, multiple sclerosis,
and diabetes. Numerous candidate gene association studies
have in turn investigated the association of specific genes
within these chromosomal regions, with susceptibility to autoimmune
diseases (e.g. FcgammaReceptors, TYK2 and systemic
lupus).
More recently, large-scale differential gene expression studies
performed on selected tissues from patients with autoimmune
disorders, have led to the identification of gene signatures
associated with the activation of specific pathways in these
diseases (e.g. interferon signature in lupus). In the future,
integrated analyses of gene (and protein) expression together
with SNP data will allow us to sketch an intelligible picture
of the genesis of autoimmunity in humans. This review sets
out to illustrate how the most recent advances in the field
of systemic lupus erythematosus, rheumatoid arthritis and
juvenile arthritis have led to a better understanding of these
disorders.
[Back to top]
[Purchase Article]
Peroxisome Proliferator-Activated Receptor-γ
(PPAR-γ)
Ligands: Novel Pharmacological Agents in the Treatment of
Ischemia Reperfusion Injury
Costas Giaginis, Gerasimos Tsourouflis and
Stamatios Theocharis
Peroxisome proliferator-activated receptor-γ
(PPAR-γ)
ligands constitute important insulin sensitizers that have
already been used for the treatment of human metabolic disorders,
exerting also pleiotropic effects on inflammatory related
diseases and cancer. Ischemia-reperfusion injury that is mainly
associated with organ transplantation constitutes a serious
complication with a great relevance in clinical practice.
Accumulating experimental data have recently revealed that
natural and synthetic PPAR-γ
ligands exert beneficial effects against ischemia-reperfusion
injury. The present review summarizes the available information
on the role of PPAR-γ
ligands in ischemia-reperfusion injury amongst the different
organ systems. Taking into consideration the data so far,
PPAR-γ
ligands seem to represent potential therapeutic agents in
the aim to reduce or even prevent injury associated with ischemia-reperfusion.
[Back to top]
[Purchase Article]
The Many Faces of Amyloid β
in Alzheimer's Disease
Peter K. Chiang, Michael A. Lam and
Yuan Luo
The 'amyloid cascade hypothesis' links amyloid β
peptide (Aβ)
with the pathological process of Alzheimer’s disease
(AD) and it still awaits universal acceptance. Amyloid precursor
protein (APP), through the actions of the γ-secretase
complex, eventually becomes a different Aβ
species. The various Aβ
species have proven to be difficult to investigate under physiological
conditions, and the species of Aβ
responsible for neurotoxicity has yet to be unequivocally
identified. The two important Aβ
peptides involved are Aβ1-40
and Aβ1-42,
and each has been ascribed both toxic and beneficial attributes.
The ratio between the two species can be important in AD etiology.
Additionally, shorter variants of Aβ
peptides such as Aβ1-8,
Aβ9-16
and Aβ16
have also been shown to be potential participants in AD pathology.
Interestingly, a new 56-kDa Aβ
peptide (Aβ*56)
disrupts memory when injected into the brains of young rats.
Transgenic mice models are complicated by the interplay between
various human Aβ
types and the mouse Aβ
types in the mouse brains. However, the accumulation of Aβ1-42
in the brains of transgenic C. elegans worms and
Drosophila is indeed detrimental. A less investigated
aspect of AD is epigenetics, but in time the investigation
of the role of epigenetics in AD may add to our understanding
of the development of AD.
[Back to top]
[Purchase Article]
Targeting Eosinophils in Asthma
Paul S. Foster, Helene F. Rosenberg, Kelly
L. Asquith and Rakesh K. Kumar
Recruitment of eosinophils has long been recognized as
a hallmark of the inflammatory response in asthma. However,
the functions of this population of cells in host defense
remain poorly understood. Eosinophils play an important part
in the inflammatory response and have key regulatory roles
in the afferent arm of the immune response. More recently,
eosinophils have been demonstrated to participate in host
defense against respiratory viruses. The specific contributions
of eosinophils to the pathophysiology of asthma remain controversial.
However, the balance of evidence indicates that they have
a significant role in the disease, suggesting that they may
be appropriate targets for therapy. Towards this end, a novel
intervention of considerable potential interest is the use
of an antibody directed against the β
common chain of the receptor for interleukin-3, interleukin-5
and granulocyte-macrophage colony-stimulating factor. However,
eliminating eosinophils may not be a risk-free therapeutic
strategy, as there is potentially an increased likelihood
of respiratory viral infec-tions. This may predispose to the
development of acute exacerbations of asthma, an outcome that
would have significant clinical implications.
|
