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Current
Genomics
ISSN: 1389-2029
Current Genomics
Volume 7, Number 5, August 2006
Contents
What Have We Learned from the Novel Human Cytochromes
P450 Hidden in the Databases? Pp. 273-282
C. Cauffiez
[Abstract]
Contemporary Progress in Gene Structure Prediction
Pp. 283-292
A. Churbanov
[Abstract]
Definition of Genes and Paths Involved in Alzheimer’s
Disease: Using Gene Expression Profiles and Chemical Genetics
at the Mouse Brain Level Pp. 293-300
P. Wu and Y. Hu
[Abstract]
S-Nitrosylation: Targets, Controls and
Outcomes Pp. 301-310
B.C. Kone
[Abstract]
Double-Strand Breaks Repair by Non-Homologous DNA
End Joining in Mammalian Cells Pp. 311-322
M. Malinowski and E. Pastwa
[Abstract]
Integrins and Cancer: Gene Expression, Epigenetics
and Metastasis Pp. 323-331
T. Stuardi, S.M.O. Phipps and T.O. Tollefsbol
[Abstract]
Abstracts
[Back to top]
What Have We Learned from the Novel Human Cytochromes
P450 Hidden in the Databases?
C. Cauffiez
Cytochromes P450 (P450s or CYPs) constitute
a superfamily of heme-containing monooxygenases and have been
shown to play a major role in both xenobiotic and endogenous
metabolism. Thanks to the Human Genome Project, the current
list of human CYPs should be exhaustive and so far 57 P450
encoding genes have been identified. To date, fifteen of them,
generally called "orphans" cytochromes P450, which
were mainly identified by homology research between the sequences
of known P450s and genomic sequences or ESTs (Expressed Sequence
Tags) databases, are not fully characterized. However, tissue
distribution, catalytic properties and physiological functions
of these "novel P450s" are being analysed and partial
results are already available for some of them, including
CYP2 (CYP2A13, CYP2R1, CYP2S1, CYP2U1 and CYP2W1), CYP3 (CYP3A43)
and CYP4 (CYP4A22, CYP4F12, CYP4F22, CYP4V2, CYP4X1, CYP4Z1)
family members. In this review, we present some of the current
data characterizing these P450s and discuss their potential
involvement in xenobiotic toxicity and carcinogenesis, as
well as their physiological relevance in pathology susceptibility.
[Back to top]
Contemporary Progress in Gene Structure
Prediction
A. Churbanov
Despite substantial recent progress, gene structural
prediction remains a challenging problem in bioinformatics.
The importance of a detailed understanding of gene splicing
can be underlined by noting that ~ 10-15% of human genetic
diseases are caused by mutations that affect splice junctions.
We briefly introduce the problem, mention the existing approaches
to gene structural annotation and provide overview of current
methods. In particular, this paper explains why homology-based
gene structural prediction appears to be more difficult then
it might seem. The problem of splice sites (SSs) sensor design
is overviewed with rigorous comparison of key designs. Finally,
a discussion of methods in ab initio gene structural
prediction is accompanied by an extensive comparative performance
study. We make certain conclusions regarding the current state
of the art and try to speculate about future research directions.
Applications used to evaluate performance characteristics
for various gene structural prediction programs are available
online at http://www.wyomingbioinformatics.org/~achurban/.
[Back to top]
Definition of Genes and Paths Involved in
Alzheimer’s Disease: Using Gene Expression Profiles
and Chemical Genetics at the Mouse Brain Level
P. Wu and Y. Hu
Gene expression profiling of a number of distinct
brain regions under different behavioral and biological states
was analyzed using DNA microarray technology. These included
hippocampal development, aging process, environmental enrichment,
fear conditioning, and calorie restriction. Our results identified
numerous genes and signal pathways that may play critical
roles in learning and memory, brain aging and longevity. Furthermore,
chemical genetic approach combined with gene expression profiling
analysis was applied to study the molecular mechanisms that
contribute to brain dysfunction including Alzheimer’s
diseases, neuronal degeneration and brain aging. These studies
not only revealed that a number of genes and signal pathways
may have participated in the pathological processes of the
brain diseases, but also contributed to the identification
of therapeutic targets for drug screening and development.
[Back to top]
S-Nitrosylation: Targets,
Controls and Outcomes
B.C. Kone
Nitric oxide (NO) is a potent cell signaling
and effector molecule that participates in numerous physiological
and pathophysiological events in a variety of cell types and
tissues. NO derived from all major isoforms of NO synthase
can S-nitrosylate cysteine thiols in target proteins,
potentially altering their functional activities in a redox-dependent,
cGMP-independent manner. Formation of protein S-nitrosocysteine
adducts appears to occur through multiple pathways. Emerging
evidence suggests that S-nitrosylation is a specific,
reversible and regulated covalent post-translational modification
that modulates diverse biological and physiological functions.
In addition to altering protein activity, localization and
stability, S-nitrosylation participates in the control
of cellular metabolism, apoptosis, protein–protein interactions,
transcription factor function, ion channel activity and cellular
redox balance. Increasingly sophisticated proteomic approaches
used in various cell types and tissues have identified S-nitrosylation
of proteins of virtually all major classes, including cytoskeletal
proteins, chaperones, proteins of the translational and transcriptional
machinery, vesicular transport and signaling. S-nitrosylation
has also been shown to regulate the NO synthase isoforms themselves,
reversibly inhibiting endothelial NO synthase activity and
feedback inhibiting PARP-1, a transactivator of inducible
NO synthase. Imbalances in NO metabolism and dysregulated
S-nitrosylation have been implicated in a growing
list of human diseases, such as neurodegenerative disorders,
endotoxemic shock and insulin resistance. Here we review the
key discoveries and directions in this field, including the
role of S-nitrosylation as a potential therapeutic
target in specific human diseases.
[Back to top]
Double-Strand Breaks Repair by Non-Homologous
DNA End Joining in Mammalian Cells
M. Malinowski and E. Pastwa
DNA double-strand breaks (DSBs) are a common
form of DNA damage and double-strand break rejoining is a
fundamental mechanism of genome protection to prevent chromosomal
fragmentation, translocation and deletions. DSBs may be induced
by exogenous agents, such as ionizing radiation, but also
occur spontaneously during cellular processes e.g.
in the rearrangement of gene segments during V(D)J [variable
(V), diversity (D), joining (J)]
recombination. The genomic instability resulting from incorrectly
repaired DSBs can lead to carcinogenesis, while unrepaired
may carry on even to cell death. To repair this potentially
lethal damage cells developed several different types of repair
act on the DSBs e.g. homologous recombination repair
(HRR), non-homologous DNA end joining (NHEJ), and single-strand
annealing (SSA).The most essential in mammalian cells is NHEJ,
whereas HRR and SSA significantly contributes to DSBs repair
in lower eukaryotes. At least six distinct proteins are known
to be required for NHEJ, including Ku70, Ku80, DNA-PKcs,
XRCC4, DNA ligase IV, and Artemis.
In this review we highlight classical and up-to-date aspects
and present understanding of the molecular mechanisms of NHEJ
in the maintenance of genome integrity.
[Back to top]
Integrins and Cancer: Gene Expression,
Epigenetics and Metastasis
T. Stuardi, S.M.O. Phipps and T.O. Tollefsbol
Integrins are composed of a variety of binding subunits
that are responsible for interacting with the extracellular
matrix and intracellular signaling pathways. Among their various
functions, integrins have the ability to augment cellular
adhesion, influence cytoskeletal architecture, activate tyrosine
kinase and affect cell survival. Many investigations have
demonstrated a correlation between the regulation of integrin
expression and tumor invasiveness and proliferation. Integrins
affect transcription factors Twist and HoxD3, epigenetic regulation,
matrix metalloproteinases, insulin-like growth factors, integrin-linked
kinases and adherens junctions, which are all important components
of tumorigenicity. Cancer cells modify their functional genomic
composition thereby altering integrin expression. Understanding
the relationship between integrin expression and tumor activities
could provide an important strategy for cancer treatment.
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