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Current
Genomics
ISSN: 1389-2029
Current Genomics
Volume 7, Number 8, December 2006
Contents
Gain-of-Function Mutations of Receptor Tyrosine Kinases
in Gastrointestinal Stromal Tumors Pp. 469-475
K. Isozaki and S. Hirota
[Abstract]
Multiple Functions of Rad9 for Preserving Genomic
Integrity Pp. 477-480
K. Ishikawa, H. Ishii, T. Saito and K. Ichimura
[Abstract]
Bacterial Stationary-State Mutagenesis and Mammalian
Tumorigenesis as Stress-Induced Cellular Adaptations and the
Role of Epigenetics Pp. 481-496
T.V. Karpinets, D.J. Greenwood, I.P. Pogribny and N.F.
Samatova
[Abstract]
Estrogen Signaling Multiple Pathways to Impact Gene
Transcription Pp. 497-508
M. Marino, P. Galluzzo and P. Ascenzi
[Abstract]
The E3 Ubiquitin Ligase Gene Family in Plants: Regulation
by Degradation Pp. 509-522
E. Mazzucotelli, S. Belloni, D. Marone, A.M. De Leonardis,
D. Guerra, N. Di Fonzo, L. Cattivelli and A.M. Mastrangelo
[Abstract]
Supplementary
Table S1
Supplementary
Table S2
Supplementary
Table S3
Molecular Classification of Breast Carcinoma In Situ
Pp. 523-532
U. Raju, M. Lu, S. Sethi, H. Qureshi, S.R. Wolman and
M.J. Worsham
[Abstract]
Abstracts
[Back to top]
Gain-of-Function Mutations of Receptor Tyrosine Kinases in
Gastrointestinal Stromal Tumors
K. Isozaki and S. Hirota
Gastrointestinal stromal tumors (GISTs) are the most
common mesenchymal tumors in human gastrointestinal tract.
We first found that most GISTs expressed KIT, a receptor tyrosine
kinase encoded by protooncogene c-kit and that approximately
90% of the sporadic GISTs had somatic gain-of-function mutations
of the c-kit gene. Since both GISTs and interstitial
cells of Cajal (ICCs) were double-positive for KIT and CD34,
GISTs were considered to originate from ICCs or their precursor
cells. We also found that germline gain-of-function mutations
of the c-kit gene resulted in familial and multiple
GISTs with diffuse hyperplasia of ICCs as the preexisting
lesion. Moreover, we found that about half of the sporadic
GISTs without c-kit gene mutations had gain-of-function
mutations of platelet-derived growth factor receptor alpha
(PDGFRA) gene that encodes another receptor tyrosine kinase.
Imatinib which is known to inhibit constitutively activated
BCR-ABL tyrosine kinase in chronic myelogenous leukemia also
inhibits constitutive activation of mutated KIT and PDGFRA,
and is now being used for metastatic or unresectable GISTs
as a molecular target drug. Mutational analyses of c-kit
and PDGFRA genes are considered to be significant for prediction
of effectiveness of imatinib and newly developed/developing
other agents on GISTs. Some mouse models of familial and multiple
GISTs have been genetically created, and may be useful for
further investigation of GIST biology.
[Back to top]
Multiple Functions of Rad9 for Preserving Genomic
Integrity
K. Ishikawa, H. Ishii, T. Saito and K. Ichimura
DNA-damage checkpoints sense and respond to genomic damage.
Human Rad9 (hRad9), an evolutionarily conserved gene with
multiple functions for preserving genomic integrity, plays
multiple roles in fundamental biological processes, including
the regulation of the DNA damage response, cell cycle checkpoint
control, DNA repair, apoptosis, transcriptional regulation,
exonuclease activity, ribonucleotide synthesis and embryogenesis.
This review examines work that provides significant insight
into the molecular mechanisms of several individual cellular
processes which might be beneficial for developing novel therapeutic
approaches to cancerous diseases with genomic instability.
[Back to top]
Bacterial Stationary-State Mutagenesis and Mammalian
Tumorigenesis as Stress-Induced Cellular Adaptations and the
Role of Epigenetics
T.V. Karpinets, D.J. Greenwood, I.P. Pogribny and N.F.
Samatova
Mechanisms of cellular adaptation may have some commonalities
across different organisms. Revealing these common mechanisms
may provide insight in the organismal level of adaptation
and suggest solutions to important problems related to the
adaptation. An increased rate of mutations, referred as the
mutator phenotype, and beneficial nature of these mutations
are common features of the bacterial stationary-state mutagenesis
and of the tumorigenic transformations in mammalian cells.
We argue that these commonalities of mammalian and bacterial
cells result from their stress-induced adaptation that may
be described in terms of a common model. Specifically, in
both organisms the mutator phenotype is activated in a subpopulation
of proliferating stressed cells as a strategy to survival.
This strategy is an alternative to other survival strategies,
such as senescence and programmed cell death, which are also
activated in the stressed cells by different subpopulations.
Sustained stress-related proliferative signalling and epigenetic
mechanisms play a decisive role in the choice of the mutator
phenotype survival strategy in the cells. They reprogram cellular
functions by epigenetic silencing of cell-cycle inhibitors,
DNA repair, programmed cell death, and by activation of repetitive
DNA elements. This reprogramming leads to the mutator phenotype
that is implemented by error-prone cell divisions with the
involvement of Y family polymerases. Studies supporting the
proposed model of stress-induced cellular adaptation are discussed.
Cellular mechanisms involved in the bacterial stress-induced
adaptation are considered in more detail.
[Back to top]
Estrogen Signaling Multiple Pathways to Impact Gene
Transcription
M. Marino, P. Galluzzo and P. Ascenzi
Steroid hormones exert profound effects on cell growth, development,
differentiation, and homeostasis. Their effects are mediated
through specific intracellular steroid receptors that act
via multiple mechanisms. Among others, the action
mechanism starting upon 17β-estradiol
(E2) binds to its receptors (ER) is considered a paradigmatic
example of how steroid hormones function. Ligand-activated
ER dimerizes and translocates in the nucleus where it recognizes
specific hormone response elements located in or near promoter
DNA regions of target genes. Behind the classical genomic
mechanism shared with other steroid hormones, E2 also modulates
gene expression by a second indirect mechanism that involves
the interaction of ER with other transcription factors which,
in turn, bind their cognate DNA elements. In this case, ER
modulates the activities of transcription factors such as
the activator protein (AP)-1, nuclear factor-κB
(NF-κB)
and stimulating protein-1 (Sp-1), by stabilizing DNA-protein
complexes and/or recruiting co-activators. In addition, E2
binding to ER may also exert rapid actions that start with
the activation of a variety of signal transduction pathways
(e.g. ERK/MAPK, p38/MAPK, PI3K/AKT, PLC/PKC). The
debate about the contribution of different ER-mediated signaling
pathways to coordinate the expression of specific sets of
genes is still open. This review will focus on the recent
knowledge about the mechanism by which ERs regulate the expression
of target genes and the emerging field of integration of membrane
and nuclear receptor signaling, giving examples of the ways
by which the genomic and non-genomic actions of ERs on target
genes converge.
[Back to top]
The E3 Ubiquitin Ligase Gene Family in Plants: Regulation
by Degradation
E. Mazzucotelli, S. Belloni, D. Marone, A.M. De Leonardis,
D. Guerra, N. Di Fonzo, L. Cattivelli and A.M. Mastrangelo
The regulation of protein expression and activity has been
for long time considered only in terms of transcription/translation
efficiency. In the last years, the discovery of post-transcriptional
and post-translational regulation mechanisms pointed out that
the key factor in determining transcript/protein amount is
the synthesis/degradation ratio, together with post-translational
modifications of proteins. Polyubiquitinaytion marks target
proteins directed to degradation mediated by 26S-proteasome.
Recent functional genomics studies pointed out that about
5% of Arabidopsis genome codes for proteins of ubiquitination
pathway. The most of them (more than one thousand genes) correspond
to E3 ubiquitin ligases that specifically recognise target
proteins. The huge size of this gene family, whose members
are involved in regulation of a number of biological processes
including hormonal control of vegetative growth, plant reproduction,
light response, biotic and abiotic stress tolerance and DNA
repair, indicates a major role for protein degradation in
control of plant life.
Supplementary
Table S1
Supplementary
Table S2
Supplementary
Table S3
[Back to top]
Molecular Classification of Breast Carcinoma In
Situ
U. Raju, M. Lu, S. Sethi, H. Qureshi, S.R. Wolman and
M.J. Worsham
Pleomorphic variant of invasive lobular carcinoma
(PILC) is an aggressive variant of invasive lobular carcinoma
(ILC). Its in situ counterpart, pleomorphic lobular
carcinoma in situ (PLCIS) is a recently described
entity. Morphologically it has the typical architectural pattern
of LCIS, but the neoplastic cells resemble intermediate grade
DCIS. Molecular signatures that distinguish PLCIS from DCIS
and LCIS would provide additional tools to aid in the histopathologic
classification of PLCIS as a lesion distinct from LCIS and
DCIS. CIS lesions, obtained from a study cohort of 38 breast
cancer patients, were divided into 18 DCIS, 14 PLCIS and 6
LCIS. DNA from microdissected archival tissue was interrogated
for loss or gain of 112 breast-cancer-specific genes using
the Multiplex Ligation-dependent Probe Amplification Assay
(MLPA). Classification Regression Tree (CART) analysis was
employed to develop a gene-based molecular classification
to distinguish or separate out PLCIS from DCIS and LCIS. Molecular
classification via CART, based on gene copy number,
agreed with histopathology in 34/38 CIS cases. Loss of CASP1
was predictive of LCIS (n=4) with one misclassified PLCIS.
Gain of RELA predicted only the LCIS classification
(n=2 cases). STK15 and TNFRSF1B were predictive
only for DCIS with no misclassifications. Gain of EHF
and TNFRSF1B and loss of NCOA3 were predictive
of PLCIS, but not without misclassification. Molecular reclassification
by CART was accomplished in 4 CIS cases: 1 PLCIS was reclassified
as LCIS, 1 LCIS reclassified as PLCIS, and 2 DCIS cases as
PLCIS. This study provides additional rationale for molecular
modeling strategies in the evaluation of CIS lesions. This
diagnostic aid may serve to minimize misclassification between
PLCIS and DCIS, and PLCIS and LCIS, aiding to increase accuracy
in the differential diagnosis of CIS lesions.
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