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Current Molecular Medicine
ISSN: 1566-5240
Current Molecular Medicine
Volume 6, Number 8, December 2006
Contents
The Multifaceted Roles of Osteopontin in Cell
Signaling, Tumor Progression and Angiogenesis Pp.
819-830
Goutam Chakraborty, Shalini Jain, Reeti Behera, Mansoor
Ahmed, Priyanka Sharma, Vinit Kumar and Gopal C. Kundu
[Abstract]
Immunomodulatory Role of Vascular Endothelial Growth
Factor and Angiopoietin-1 in Airway Remodeling Pp.
831-841
Toluwalope Makinde, Richard F. Murphy and Devendra K.
Agrawal
[Abstract]
Costimulatory Molecules as Targets for the Induction
of Transplantation Tolerance Pp. 843-857
Maria-Luisa Alegre and Nader Najafian
[Abstract]
Blood Coagulation and Alternative Pre-mRNA Splicing:
An Overview Pp. 859-869
Vladimir Y. Bogdanov
[Abstract]
Modeling Oxidative Stress in the Central Nervous System
Pp. 871-881
Maria K. Lehtinen and Azad Bonni
[Abstract]
Role of HIF-1 in Iron Regulation: Potential Therapeutic
Strategy for Neurodegenerative Disorders Pp. 883-893
Donna W. Lee and Julie K. Andersen
[Abstract]
Plasma Membrane Electron Transport: A New Target for
Cancer Drug Development Pp. 895-904
Patries M. Herst and Michael V. Berridge
[Abstract]
Notch Signaling in Cancer Pp. 905-918
Lucio Miele, Todd Golde and Barbara Osborne
[Abstract]
Abstracts
[Back to top]
The Multifaceted Roles of Osteopontin in Cell Signaling, Tumor
Progression and Angiogenesis
Goutam Chakraborty, Shalini Jain, Reeti Behera, Mansoor
Ahmed, Priyanka Sharma, Vinit Kumar and Gopal C. Kundu
Osteopontin (OPN) is a chemokine like phosphorylated glycoprotein
that plays important role in cancer progression. Extensive
research from various laboratories has demonstrated the likely
role of OPN in regulating the cell signaling that ultimately
controls tumor growth and metastasis. Several earlier reports
indicated that OPN is associated with various cancers; but
its functional role in carcinogenesis is still not well defined.
Besides the role of OPN in tumor biology, several studies
have demonstrated the pathophysiological role of OPN in diverse
biological events. This review will focus on recent advances
in understanding the molecular mechanism by which OPN regulates
a series of signaling cascades through activation of various
kinases and transcription factors that ultimately control
the expression of downstream effector genes, which contribute
to tumor progression and angiogenesis in vitro and
animal models. We will also provide evidences that suggest
the enhanced expression of OPN is not only associated with
several tumor types, but its level of expression is directly
correlated to various stages of the clinical specimens of
breast and prostate cancers. These studies may be useful for
identifying novel OPN-based therapeutic approach for the treatment
of cancer.
[Back to top]
Immunomodulatory Role of Vascular Endothelial Growth
Factor and Angiopoietin-1 in Airway Remodeling
Toluwalope Makinde, Richard F. Murphy and Devendra K.
Agrawal
The blood vessels formed in asthmatic airways are involved
in inflammatory and airway remodeling processes in chronic
asthma. Vascular endothelial cell growth factor (VEGF) and
angiopoietin-1 (Ang-1) are primary angiogenic growth factors,
involved in the formation of such blood vessels. VEGF has
been reported to contribute to non-specific airway hyper-responsiveness,
have chemotactic effects on eosinophils, and enhance airway
smooth muscle cell proliferation. Furthermore, Th2 cells have
receptors for VEGF, and Th2-associated cytokines increase
VEGF production. There are reports that elevated levels of
VEGF correlates with the severity of asthma. Ang-1 has been
shown to induce pro-inflammatory effects such as eosinophil
chemotaxis via tie-2 receptors. Reports indicate
ang-1 contribution to increased secretion of matrix metalloproteinase-2
(MMP-2) and decreased secretion of tissue inhibitors of metalloproteinase-2
(TIMP-2). However, Ang-1 has also been shown to exhibit several
anti-inflammatory properties such as suppressing expression
of adhesion molecules, blocking vascular permeability and
eosinophil chemotaxis induced by VEGF. These findings support
the notion that apart from their roles in blood vessels formation,
these angiogenic growth factors are directly involved in the
pathogenesis of chronic asthma. This paper reviews individual
and combined roles of VEGF and Ang-1. The potential therapeutic
applications involving these factors are also discussed.
[Back to top]
Costimulatory Molecules as Targets for the Induction
of Transplantation Tolerance
Maria-Luisa Alegre and Nader Najafian
Transplantation is the only cure for end-stage organ failure.
Transplanted tissues are usually recognized by the immune
system as foreign and are rapidly rejected in the absence
of immunosuppression. Transplanted organs between genetically
distinct individuals are termed allografts and their acute
rejection is orchestrated by the activation of allospecific
T cells. To prevent acute allograft rejection, current therapies
suppress all T cells irrespective of their specificities and
must be taken life-long, leaving patients with decreased defenses
against infectious agents and cancers. The goal in transplantation
research is to develop therapies with the capacity to induce
graft-specific tolerance. Ideal therapies should be of short
duration and target only alloreactive T cells, leaving other
T cells competent to fight infections and cancers. Researchers
have studied the mechanisms of activation/regulation of T
cells in the hopes that manipulation of these pathways may
facilitate the induction of tolerance. Activation of T cells
requires recognition by the T cell receptor (TCR) of antigenic
peptides presented within major histocompatibility complexes
(MHC) on the surface of antigen-presenting cells (APCs). In
addition, concurrent engagement of costimulatory receptors
on T cells by ligands on APCs is also required for optimal
T cell responses, such that the ultimate outcome of TCR engagement
reflects the relative sum of multiple positive and negative
costimulatory signals. Targeting costimulatory receptor/ligand
pairs has been used effectively to induce allograft tolerance
in specific rodent transplantation models. This strategy has
however been less effective in larger mammals. In this review,
we will summarize the different reagents used to target costimulatory
molecules, their effects, and the possible reasons limiting
their efficacy in higher order mammals.
[Back to top]
Blood Coagulation and Alternative Pre-mRNA Splicing:
An Overview
Vladimir Y. Bogdanov
Throughout the 20th century, great advances were
made in understanding of how blood coagulation occurs, what
physiological and biochemical mechanisms are responsible for
its regulation, and what genes and their protein products
comprise the essential components of the hemostatic network.
Recently, complete sequencing of the human genome revealed
that the structural diversity of higher eukaryotes cannot
be solely attributed to the number of protein-encoding genes,
whereas tools of molecular biology helped establish that pre-mRNAs
produced by most protein-encoding genes undergo alternative
splicing, a mechanism that enables production of multiple
protein isoforms by a single gene. Research in the field of
thrombosis and hemostasis revealed that the genes encoding
several critical proteins at various junctures of the coagulation
cascade produce alternatively spliced protein isoforms with
distinct structural and biochemical characteristics, revealing
a principally novel dimension in the regulation of blood clotting
and, possibly, a few novel therapeutic approaches to treatment
of abnormal hemostasis. This review summarizes recently published
data pertaining to biosynthesis of the alternatively spliced
isoforms of tissue factor (TF, or coagulation factor III),
tissue factor pathway inhibitor (TFPI), and coagulation factor
XI (FXI), and discusses future directions of this continuously
evolving area of biomedical research, with an emphasis on
molecular mechanics responsible for regulation of constitutive
as well as alternative pre-mRNA splicing.
[Back to top]
Modeling Oxidative Stress in the Central Nervous System
Maria K. Lehtinen and Azad Bonni
Oxidative stress is associated with the onset and pathogenesis
of several prominent central nervous system disorders. Consequently,
there is a pressing need for experimental methods for studying
neuronal responses to oxidative stress. A number of techniques
for modeling oxidative stress have been developed, including
the use of inhibitors of the mitochondrial respiratory chain,
depletion of endogenous antioxidants, application of products
of lipid peroxidation, use of heavy metals, and models of
ischemic brain injury. These experimental approaches can be
applied from cell culture to in vivo animal models.
Their use has provided insight into the molecular underpinnings
of oxidative stress responses in the nervous system, including
cell recovery and cell death. Reactive oxygen species contribute
to conformational change-induced activation of signaling pathways,
inactivation of enzymes through modification of catalytic
cysteine residues, and subcellular redistribution of signaling
molecules. In this review, we will discuss several methods
for inducing oxidative stress in the nervous system and explore
newly emerging concepts in oxidative stress signaling.
[Back to top]
Role of HIF-1 in Iron Regulation: Potential Therapeutic
Strategy for Neurodegenerative Disorders
Donna W. Lee and Julie K. Andersen
A disruption in optimal iron levels within different brain
regions has been demonstrated in several neurodegenerative
disorders. Although iron is an essential element that is required
for many processes in the human body, an excess can lead to
the generation of free radicals that can damage cells. Iron
levels are therefore stringently regulated within cells by
a host of regulatory proteins that keep iron levels in check.
The iron regulatory proteins (IRPs) have the ability to sense
and control the level of intracellular iron by binding to
iron responsive elements (IREs) of several genes encoding
key proteins such as the transferrin receptor (TfR) and ferritin.
Concurrently, the hypoxia-inducible factor (HIF) has also
been shown in previous studies to regulate intracellular iron
by binding to HIF-responsive elements (HREs) that are located
within the genes of iron-related proteins such as TfR and
heme oxygenase-1 (HO-1). This review will focus on the interactions
between the IRP/IRE and HIF/HRE systems and how cells utilize
these intricate networks to regulate intracellular iron levels.
Additionally, since iron chelation has been suggested to be
a therapeutic treatment for disorders such as Parkinson’s
and Alzheimer’s disease, understanding the exact mechanisms
by which iron acts to cause disease and how the brain would
be impacted by iron chelation could potentially give us novel
insights into new therapies directed towards preventing or
slowing neuronal cell loss associated with these disorders.
[Back to top]
Plasma Membrane Electron Transport: A New Target for
Cancer Drug Development
Patries M. Herst and Michael V. Berridge
The view that mitochondrial electron transport is the only
site of aerobic respiration and the primary bioenergetic pathway
in mammalian cells is well established in the literature.
Although this paradigm is widely accepted for most tissues,
the situation is less clear for proliferating cells. Increasing
evidence indicates that glycolytic ATP production contributes
substantially to fulfilling the energy requirements of rapidly
dividing somatic cells, many tumour cells, and self-renewing
stem cells in hypoxic environments. Glycolytic cells have
been shown to consume oxygen at the cell surface via
plasma membrane electron transport (PMET), a process that
oxidises intracellular NADH, supports glycolytic ATP production
and may contribute to aerobic energy production. PMET, as
determined by reduction of a cell-impermeable tetrazolium
dye, is highly active in rapidly-dividing tumour cell lines,
where it ameliorates intracellular reductive stress, originating
from the mitochondrial TCA cycle. Thus, mitochondrial NADH
production is linked to dye reduction outside the cell via
the malate-aspartate shuttle. PMET activity increases several-fold
under hypoxic conditions, consistent with the view that oxygen
competes for electrons from this PMET system. In addition,
ρº
cells that lack mitochondrial electron transport are characterised
by elevated PMET presumably to recycle NADH, a role traditionally
assumed by lactate dehydrogenase. PMET presents an excellent
target for developing novel anticancer drugs that exploit
its unique plasma membrane localisation. We propose that PMET
is a ubiquitous, high-capacity acute NADH redox-regulatory
system responsible for maintaining the mitochondrial NADH/NAD+
ratio. Blocking this pathway compromises the viability of
rapidly proliferating cells that rely on PMET.
[Back to top]
Notch Signaling in Cancer
Lucio Miele, Todd Golde and Barbara Osborne
The evolutionarily conserved developmental pathway driven
by Notch receptors and ligands has acquired multiple post-natal
homeostatic functions in vertebrates. Potential roles in human
physiology and pathology are being studied by an increasingly
large number of investigators. While the canonical Notch signaling
pathway is deceptively simple, the consequences of Notch activation
on cell fate are complex and context-dependent. The manner
in which other signaling pathways cross-talk with Notch signaling
appears to be extraordinarily complex. Recent observations
have demonstrated the importance of endocytosis, multiple
ubiquitin ligases, non-visual β-arrestins
and hypoxia in modulating Notch signaling. Structural biology
is shedding light on the molecular mechanisms whereby Notch
interacts with its nuclear partners. Genomics is slowly unraveling
the puzzle of Notch target genes in several systems. At the
same time, interest in modulating Notch signaling for medical
purposes has dramatically increased. Over the last few years
we have learned much about Notch signaling in cancer, immune
disorders, neurological disorders and most recently, stroke.
The role of Notch signaling in normal and transformed stem
cells is under intense investigation. Some Notch-modulating
drugs are already in clinical trials, and others at various
stages of development. This review will focus on the most
recent findings on Notch signaling in cancer and discuss their
potential clinical implications.
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