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Current
Genomics
ISSN: 1389-2029
Current Genomics
Volume 10, Number 4, June 2009
Contents
Signaling Transduction Network Mediated by Tumor Suppressor/
Susceptibility Genes in NPC Pp. 216-222
M. Wu, X. Li, X. Li and G. Li
[Abstract] [Purchase
Article]
Control of the Bone Morphogenetic Protein
7 Gene in Developmental and Adult Life Pp. 223-230
L. Oxburgh
[Abstract] [Purchase
Article]
Molecular Markers of Tumor Progression
in Melanoma Pp. 231-239
J. Rother and D. Jone
[Abstract] [Purchase
Article]
An Outlook on Ovarian Cancer and Borderline
Ovarian Tumors: Focus on Genomic and Proteomic Findings Pp.
240-249
A. Tinelli, D. Vergara, R. Martignago, G. Leo,
M. Pisanò and A. Malvasi
[Abstract] [Purchase
Article]
Involvement of Nucleotide Excision and
Mismatch Repair Mechanisms in Double Strand Break Repair Pp.
250-258
Y. Zhang, L.H. Rohde and H. Wu
[Abstract] [Purchase
Article]
Mouse Models of Genomic Syndromes as Tools for Understanding
the Basis of Complex Traits: An Example with the Smith-Magenis
and the Potocki-Lupski Syndromes Pp. 259-268
P. Carmona-Mora, J. Molina, C.A. Encina and
K. Walz
[Abstract] [Purchase
Article]
Gene Expression and Regulation of Higher
Plants Under Soil Water Stress Pp. 269-280
F.-T. Ni, L.-Y. Chu, H.-B. Shao and
Z.-H. Liu
[Abstract] [Purchase
Article]
Mitochondrial and Nuclear Genes of Mitochondrial
Components in Cancer Pp. 281-293
E. Kirches
[Abstract] [Purchase
Article]
Abstracts
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Signaling Transduction Network Mediated by Tumor Suppressor/
Susceptibility Genes in NPC
M. Wu, X. Li, X. Li and G. Li
Nasopharyngeal carcinoma (NPC) is a polygenetic disease.
SPLUNC1, UBAP1, BRD7, NAG7, NOR1, NGX6 and LTF genes were
found to be tumor suppressor/susceptibility genes in different
stages of NPC. SPLUNC1, an early warning molecular diagnosis
marker, inhibits the bacteria clone formation, and is an innated
immune molecule. SPLUNC1 can negatively regulate the ERK/MAPK
signaling transduction pathway to inhibit NPC cell proliferation
and induce apoptosis. BRD7, a transcript regulation factor,
interacts with BRD2, and promotes apoptosis induced by BRD2.
Its promoter is regulated by c-Myc and SP1. BRD7 inhibits
NPC cell cycle progression, preventing passage through G0/G1
by suppressing ras/MEK/ERK, Rb/E2F and Wnt signaling pathways.
Abnormal activation of BRD7 is crucial to cell cycle turbulence
in NPC. NGX6, a metastasis-associated protein, can negative-regulate
the EGF/Ras/MAPK signaling transduction pathway, and interacts
with ezrin protein to inhibit NPC cell invasion and metastasis.
LTF, also a metastasisassociated protein, can negatively regulate
MAPK signal transduction pathways, such as JNK2 and ERK, to
inhibit NPC cell proliferation and growth. Taken together,
it was found that these tumor suppressor/susceptibility genes
can regulate key molecules involved in cell signal pathways
such as ras/MEK/ERK, Rb/E2F and EGFR ras/MEK/MAPK, and can
regulate the expression of some adhesion molecules such as
ezrin, nm23 and α-catenin.
According to functional genomics and signaling transduction
pathways, we have described a signaling cross-talk network
between the tumor suppressor/susceptibility genes involved
in NPC. These tumor suppressor/susceptibility genes may be
potential treatment targets for NPC in the future.
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Control of the Bone Morphogenetic Protein 7 Gene in Developmental
and Adult Life
L. Oxburgh
The TGFβ
superfamily growth factor BMP7 performs essential biological
functions in embryonic development and regeneration of injured
tissue in the adult. BMP7 activity is regulated at numerous
levels in the signaling pathway by the expression of extracellular
antagonists, decoy receptors and inhibitory cell signaling
components. Additionally, expression of the BMP7
gene is tightly controlled both during embryonic development
and adult life. In this review, the current status of work
on regulation of BMP7 at the genomic level is discussed.
In situ hybridization and reporter gene studies have
conclusively defined patterns of BMP7 expression
in many tissues. Additionally, both in vivo and cell
culture studies have defined some of the mechanistic bases
for this regulation. In addition to transcriptional activation
mediated by binding of activating transcription factors, there
is also strong evidence for repression through recruitment
of histone modifying enzymes to specific genetic elements.
This review summarizes our current understanding of BMP7
gene regulation in embryonic development and adult tissues.
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Molecular Markers of Tumor Progression in Melanoma
J. Rother and D. Jone
Malignant melanoma represents one of the most aggressive
malignancies but outcome is highly variable with early tumor
lesions having an excellent prognosis following resection.
We review here the data on identification of genes involved
in the progression of melanoma as a result of expression array
studies, genomic profiling, and genetic models. We focus on
the role of tumor suppressors involved in cell cycle function,
DNA repair, and genome maintenance. Highlighted are the roles
of loss of p16 in promoting neoplasia in cooperation with
deregulated MAPK signaling, and the role of loss of the RASSF1A
protein in promoting chromosomal instability. The interactions
between point mutation in growth signaling molecules and epigenetic
changes in genes involved in DNA repair and cell division
are discussed.
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An Outlook on Ovarian Cancer and Borderline Ovarian Tumors:
Focus on Genomic and Proteomic Findings
A. Tinelli, D. Vergara, R. Martignago, G.
Leo, M. Pisanò and A. Malvasi
Among the gynaecological malignancies, ovarian cancer
is one of the neoplastic forms with the poorest prognosis
and with the bad overall and disease-free survival rates than
other gynaecological cancers. Ovarian tumors can be classified
on the basis of the cells of origin in epithelial, stromal
and germ cell tumors. Epithelial ovarian tumors display great
histological heterogeneity and can be further subdivided into
benign, intermediate or borderline, and invasive tumors. Several
studies on ovarian tumors, have focused on the identification
of both diagnostic and prognostic markers for applications
in clinical practice. High-throughput technologies have accelerated
the process of biomolecular study and ge-nomic discovery;
unfortunately, validity of these should be still demonstrated
by extensive researches on sensibility and sensitivity of
ovarian cancer novel biomarkers, determining whether gene
profiling and proteomics could help differentiate between
patients with metastatic ovarian cancer and primary ovarian
carcinomas, and their potential impact on management. Therefore,
considerable interest lies in identifying molecular and protein
biomarkers and indicators to guide treatment decisions and
clinical follow up. In this review, the current state of knowledge
about the genoproteomic and potential clinical value of gene
expression profiling in ovarian cancer and ovarian borderline
tumors is discussed, focusing on three main areas: distinguishing
normal ovarian tissue from ovarian cancers and borderline
tumors, identifying diffeent genotypes of ovarian tissue and
identifying proteins linked to cancer or tumor development.
By these targets, authors focus on the use of novel molecules,
developed on the proteomics and genomics researches, as potential
protein biomarkers in the management of ovarian cancer or
borderline tumor, overlooking on current state of the art
and on future perspectives of researches.
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Involvement of Nucleotide Excision and Mismatch Repair Mechanisms
in Double Strand Break Repair
Y. Zhang, L.H. Rohde and
H. Wu
Living organisms are constantly threatened by environmental
DNA-damaging agents, including UV and ionizing radiation (IR).
Repair of various forms of DNA damage caused by IR is normally
thought to follow lesion-specific repair pathways with distinct
enzymatic machinery. DNA double strand break is one of the
most serious kinds of damage induced by IR, which is repaired
through double strand break (DSB) repair mechanisms, including
homologous recombination (HR) and non-homologous end joining
(NHEJ). However, recent studies have presented increasing
evidence that various DNA repair pathways are not separated,
but well interlinked. It has been suggested that non-DSB repair
mechanisms, such as Nucleotide Excision Repair (NER), Mismatch
Repair (MMR) and cell cycle regulation, are highly involved
in DSB repairs. These findings revealed previously unrecognized
roles of various non-DSB repair genes and indicated that a
successful DSB repair requires both DSB repair mechanisms
and non-DSB repair systems. One of our recent studies found
that suppressed expression of non-DSB repair genes, such as
XPA, RPA and MLH1, influenced the yield of IR-induced micronuclei
formation and/or chromosome aberrations, suggesting that these
genes are highly involved in DSB repair and DSB-related cell
cycle arrest, which reveals new roles for these gene products
in the DNA repair network. In this review, we summarize current
progress on the function of non-DSB repair-related proteins,
especially those that participate in NER and MMR pathways,
and their influence on DSB repair. In addition, we present
our developing view that the DSB repair mechanisms are more
complex and are regulated by not only the well known HR/NHEJ
pathways, but also a systematically coordinated cellular network.
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Mouse Models of Genomic Syndromes as Tools for Understanding
the Basis of Complex Traits: An Example with the Smith-Magenis
and the Potocki-Lupski Syndromes
P. Carmona-Mora, J. Molina, C.A. Encina and
K. Walz
Each human's genome is distinguished by extra and missing
DNA that can be “benign” or powerfully impact
everything from development to disease. In the case of genomic
disorders DNA rearrangements, such as deletions or duplications,
correlate with a clinical specific phenotype. The clinical
presentations of genomic disorders were thought to result
from altered gene copy number of physically linked dosage
sensitive genes. Genomic disorders are frequent diseases (~1
per 1,000 births). Smith-Magenis syndrome (SMS) and Potocki-Lupski
syndrome (PTLS) are genomic disorders, associated with a deletion
and a duplication, of 3.7 Mb respectively, within chromosome
17 band p11.2. This region includes 23 genes. Both syndromes
have complex and distinctive phenotypes including multiple
congenital and neurobehavioral abnormalities. Human chromosome
17p11.2 is syntenic to the 32-34 cM region of murine chromosome
11. The number and order of the genes are highly conserved.
In this review, we will exemplify how genomic disorders can
be modeled in mice and the advantages that such models can
give in the study of genomic disorders in particular and gene
copy number variation (CNV) in general. The contributions
of the SMS and PTLS animal models in several aspects ranging
from more specific ones, as the definition of the clinical
aspects of the human clinical spectrum, the identification
of dosage sensitive genes related to the human syndromes,
to the more general contributions as the definition of genetic
locus impacting obesity and behavior and the elucidation of
general mechanisms related to the pathogenesis of gene CNV
are discussed.
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Gene Expression and Regulation of Higher Plants Under Soil
Water Stress
F.-T. Ni, L.-Y. Chu, H.-B. Shao and
Z.-H. Liu
Higher plants not only provide human beings renewable
food, building materials and energy, but also play the most
important role in keeping a stable environment on earth. Plants
differ from animals in many aspects, but the important is
that plants are more easily influenced by environment than
animals. Plants have a series of fine mechanisms for responding
to environmental changes, which has been established during
their long-period evolution and artificial domestication.
The machinery related to molecular biology is the most important
basis. The elucidation of it will extremely and purposefully
promote the sustainable utilization of plant resources and
make the best use of its current potential under different
scales. This molecular mechanism at least includes drought
signal recognition (input), signal transduction (many cascade
biochemical reactions are involved in this process), signal
output, signal responses and phenotype realization, which
is a multi-dimension network system and contains many levels
of gene expression and regulation. We will focus on the physiological
and molecular adaptive machinery of plants under soil water
stress and draw a possible blueprint for it. Meanwhile, the
issues and perspectives are also discussed. We conclude that
biological measures is the basic solution to solving various
types of issues in relation to sustainable development and
the plant measures is the eventual way.
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Mitochondrial and Nuclear Genes of Mitochondrial Components
in Cancer
E. Kirches
Although the observation of aerobic glycolysis of tumor
cells by Otto v. Warburg had demonstrated abnormalities of
mitochondrial energy metabolism in cancer decades ago, there
was no clear evidence for a functional role of mutant mitochondrial
proteins in cancer development until the early years of the
21st century. In the year
2000, a major break-through was achieved by the observation,
that several genes coding for subunits of the respiratory
chain (ETC) complex II, succinate dehydrogenase (SDH)
are tumor suppressor genes in heritable paragangliomas, fulfilling
Knudson’s classical two-hit hypothesis. A functional
inactivation of both alleles by germline mutations and chromosomal
losses in the tumor tissue was found in the patients. Later,
SDH mutations were also identified in sporadic paragangliomas
and pheochromocytomas. Genes of the mitochondrial ATP-synthase
and of mitochondrial iron homeostasis have been implicated
in cancer development at the level of cell culture and mouse
experiments. In contrast to the well established role of some
nuclear SDH genes, a functional impact of the mitochondrial
genome itself (mtDNA) in cancer development remains unclear.
Nevertheless, the extremely high frequency of mtDNA mutations
in solid tumors raises the question, whether this small circular
genome might be applicable to early cancer detection. This
is a meaningful approach, especially in cancers, which tend
to spread tumor cells early into bodily fluids or faeces,
which can be screened by non-invasive methods.
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