Current Genomics

ISSN: 1389-2029

Current Genomics
Volume 10, Number 8, December 2009

Contents


Telomeres and Thyroid Cancer Pp. 526-533
M. Capezzone, S. Marchisotta, S. Cantara and F. Pacini
[Abstract] [Full text article]


Current Gene Expression Studies in Esophageal Carcinoma Pp. 534-539
W. Guo and Y.-G. Jiang
[Abstract] [Full text article]


Advances in Genetical Genomics of Plants Pp. 540-549
R.V.L. Joosen, W. Ligterink, H.W.M. Hilhorst and J.J.B. Keurentjes
[Abstract] [Full text article]


Mechanisms and Signals for the Nuclear Import of Proteins Pp. 550-557
N. Freitas and C. Cunha
[Abstract] [Full text article]


Getting a Grip on Complexes Pp. 558-572
Y. Nie, C. Viola, C. Bieniossek, S. Trowitzsch, L.S. Vijayachandran, M. Chaillet, F. Garzoni and I. Berger
[Abstract] [Full text article]


Perspectives in Cell Cycle Regulation: Lessons from an Anoxic Vertebrate Pp. 573-584
K.K. Biggar and K.B. Storey
[Abstract] [Full text article]


Do mtDNA Mutations Participate in the Pathogenesis of Sporadic Parkinson’s Disease? Pp. 585-593
E. Kirches
[Abstract] [Full text article]


Krüppel-Like Factors 4 and 5: Unity in Diversity Pp. 594-603
I. Sur
[Abstract] [Full Text Article]

Abstracts


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Telomeres and Thyroid Cancer
M. Capezzone, S. Marchisotta, S. Cantara and F. Pacini

Telomeres are specialized structures at the ends of chromosomes, consisting of hundreds of repeated hexanucleotides (TTAGGG)n. Genetic integrity is partly maintained by the architecture of telomeres and it is gradually lost as telomeres progressively shorten with each cell replication, due to incomplete lagging DNA strand synthesis and oxidative damage. Telomerase is a reverse transcriptase enzyme that counteracts telomere shortening by adding telomeric repeats to the G-rich strand. It is composed of a telomerase RNA component and a protein component, telomerase reverse transcriptase. In the absence of telomerase or when the activity of the enzyme is low compared to the replicative erosion, apoptosis is triggered. Patients who have inherited genetic defects in telomere maintenance seem to have an increased risk of devel-oping familial benign diseases or malignant diseases. At the somatic level, telomerase is reactivated in the majority of human carcinomas, suggesting that telomerase reactivation is a critical step for cancerogenesis.

In sporadic thyroid carcinoma telomerase activity is detectable in nearly 50% of thyroid cancer tissues and some authors proposed that the detection of telomerase activity may be used for differentiating between benign and malignant thyroid tumours. Recently a germline alteration of telomere-telomerase complex has been identified in patients with familial pap-illary thyroid cancer, characterized by short telomeres and increased expression and activity of telomerase compared to patients with sporadic papillary thyroid cancer.

In this report, we will review the role of telomere-telomerase complex in sporadic and familial thyroid cancer.


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Current Gene Expression Studies in Esophageal Carcinoma
W. Guo and Y.-G. Jiang

Esophageal carcinoma is one of the deadliest cancers with highly aggressive potency, ranking as the sixth most common cancer among males and ninth most common cancer among females globally. Due to metastasis and invasion of surrounding tissues in early stage, the 5-year overall survival rate (14%) of esophageal cancer remains poor, even in comparison with the dismal survival rates (4%) from the 1970s. Numerous genes and proteins with abnormal expression and function involve in the pathogenesis of esophageal cancer, but the concrete process remains unclear. Microarray technique has been applied to investigating esophageal cancer. Many gene expression studies have been undertaken to look at the specific patterns of gene transcript levels in esophageal cancer. Human tissues and cell lines were used in these gene-profiling studies and a very valuable and interesting set of data has resulted from various microarray experiments. These expression studies have provided increased understanding of the complex pathological mechanisms involved in esophageal cancer. The eventual goal of microarray is to discover new markers for therapy and to customize therapy based on an individual tumor genetic composition. This review summarized the current state of gene expression profile studies in esophageal cancer.


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Advances in Genetical Genomics of Plants
R.V.L. Joosen, W. Ligterink, H.W.M. Hilhorst and J.J.B. Keurentjes

Natural variation provides a valuable resource to study the genetic regulation of quantitative traits. In quantitative trait locus (QTL) analyses this variation, captured in segregating mapping populations, is used to identify the genomic regions affecting these traits. The identification of the causal genes underlying QTLs is a major challenge for which the detection of gene expression differences is of major importance. By combining genetics with large scale expression profiling (i.e. genetical genomics), resulting in expression QTLs (eQTLs), great progress can be made in connecting phenotypic variation to genotypic diversity. In this review we discuss examples from human, mouse, Drosophila, yeast and plant research to illustrate the advances in genetical genomics, with a focus on understanding the regulatory mechanisms underlying natural variation. With their tolerance to inbreeding, short generation time and ease to generate large families, plants are ideal subjects to test new concepts in genetics. The comprehensive resources which are available for Arabidopsis make it a favorite model plant but genetical genomics also found its way to important crop species like rice, barley and wheat. We discuss eQTL profiling with respect to cis and trans regulation and show how combined studies with other ‘omics’ technologies, such as metabolomics and proteomics may further augment current information on transcriptional, translational and metabolomic signaling pathways and enable reconstruction of detailed regulatory networks. The fast developments in the ‘omics’ area will offer great potential for genetical genomics to elucidate the genotype-phenotype relationships for both fundamental and applied research.


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Mechanisms and Signals for the Nuclear Import of Proteins
N. Freitas and C. Cunha

In eukaryotes, the nuclear membrane provides a physical barrier to the passive diffusion of macromolecules from and into the cytoplasm. Nucleocytoplasmic traffic occurs through highly specialized structures known as nuclear pores, and involves the participation of a special class of transport proteins. Active transport across the nuclear pores is an energy-dependent process that relies on the activity of Ran-GTPases both in the nuclear and cytoplasmic compartments.

Nuclear import of proteins is an essential step in regulating gene expression and the replication cycle of several viruses. In this review, the key mechanisms, pathways, and models underlying the transport of proteins across nuclear pores are analysed.


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Getting a Grip on Complexes
Y. Nie, C. Viola, C. Bieniossek, S. Trowitzsch, L.S. Vijayachandran, M. Chaillet, F. Garzoni and I. Berger

We are witnessing tremendous advances in our understanding of the organization of life. Complete genomes are being deciphered with ever increasing speed and accuracy, thereby setting the stage for addressing the entire gene product repertoire of cells, towards understanding whole biological systems. Advances in bioinformatics and mass spectrometric techniques have revealed the multitude of interactions present in the proteome. Multiprotein complexes are emerging as a paramount cornerstone of biological activity, as many proteins appear to participate, stably or transiently, in large multi-subunit assemblies. Analysis of the architecture of these assemblies and their manifold interactions is imperative for understanding their function at the molecular level. Structural genomics efforts have fostered the development of many technologies towards achieving the throughput required for studying system-wide single proteins and small interaction motifs at high resolution. The present shift in focus towards large multiprotein complexes, in particular in eukaryotes, now calls for a likewise concerted effort to develop and provide new technologies that are urgently required to produce in quality and quantity the plethora of multiprotein assemblies that form the complexome, and to routinely study their structure and function at the molecular level. Current efforts towards this objective are summarized and reviewed in this contribution.


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Perspectives in Cell Cycle Regulation: Lessons from an Anoxic Vertebrate
K.K. Biggar and K.B. Storey

The ability of an animal, normally dependent on aerobic respiration, to suspend breathing and enter an anoxic state for long term survival is clearly a fascinating feat, and has been the focus of numerous biochemical studies. When anoxia tolerant turtles are faced with periods of oxygen deprivation, numerous physiological and biochemical alterations take place in order to facilitate vital reductions in ATP consumption. Such strategies include reversible post-translational modifications as well as the implementation of translation and transcription controls facilitating metabolic depression. Although it is clear that anoxic survival relies on the suppression of ATP consuming processes, the state of the cell cycle in anoxia tolerant vertebrates remain elusive. Several anoxia tolerant invertebrate and embryonic vertebrate models display cell cycle arrest when presented with anoxic stress. Despite this, the cell cycle has not yet been characterized for anoxia tolerant turtles. Understanding how vertebrates respond to anoxia can have important clinical implications. Uncontrollable cellular proliferation and hypoxic tumor progression are inescapably linked in vertebrate tissues. Consequentially, the molecular mechanisms controlling these processes have profound clinical consequences. This review article will discuss the theory of cell cycle arrest in anoxic vertebrates and more specifically, the control of the retinoblastoma pathway, the molecular markers of cell cycle arrest, the activation of checkpoint kinases, and the possibility of translational controls implemented by microRNAs.


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Do mtDNA Mutations Participate in the Pathogenesis of Sporadic Parkinson’s Disease?
E. Kirches

The pathogenesis of sporadic Parkinson’s disease (PD) remains enigmatic. Mitochondrial complex-I defects are known to occur in the substantia nigra (SN) of PD patients and are also debated in some extracerebral tissues. Early sequencing efforts of the mitochondrial DNA (mtDNA) did not reveal specific mutations, but a long lasting discussion was devoted to the issue of randomly distributed low level point mutations, caused by oxidative stress. However, a potential functional impact remained a matter of speculation, since heteroplasmy (mutational load) at any base position analyzed, remained far below the relevant functional threshold. A clearly age-dependent increase of the ‘common mtDNA deletion’ had been demonstrated in most brain regions by several authors since 1992. However, heteroplasmy did hardly exceed 1% of total mtDNA. It became necessary to exploit PCR techniques, which were able to detect any deletion in a few microdissected dopaminergic neurons of the SN. In 2006, two groups published biochemically relevant loads of somatic mtDNA deletions in these neurons. They seem to accumulate to relevant levels in the SN dopaminergic neurons of aged individuals in general, but faster in those developing PD. It is reasonable to assume that this accumulation causes mito-chondrial dysfunction of the SN, although it cannot be taken as a final proof for an early pathogenetic role of this dysfunction. Recent studies demonstrate a distribution of deletion breakpoints, which does not differ between PD, aging and classical mitochondrial disorders, suggesting a common, but yet unknown mechanism.


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Krüppel-Like Factors 4 and 5: Unity in Diversity
I. Sur

Krüppel-like factors (Klf) 4 and 5 belong to a family of zinc finger-containing transcription factors that share homology with the Drosophila gene Krüppel. They regulate proliferation and differentiation of a wide variety of cells and have been linked to tumorigenesis. Their most striking role so far has turned out to be their ability to reprogram/ maintain embryonic stem cell fate. In this review, the data available in the field regarding their role in proliferation and differentiation and their coupling to carcinogenesis are summarized. The emphasis is on their context dependence and how they might be able to regulate diverse transcriptional outputs from the genome.