Current Genomics - Volume 8, Issue 4, 2007

In mammals, the cells of the renal medulla are physiologically exposed to interstitial osmolalities several-fold higher that found in any other tissue. Nevertheless, these cells not only have the ability to survive in this harsh environment, but also to function normally, which is critical for maintenance of systemic electrolyte and fluid homeostasis. Over the last two decades, a substantial body of evidence has accumulated, indicating that sequential and well orchestrated genomic responses are required to provide tolerance to osmotic stress. This includes the enhanced expression and action of immediate-early genes, growth arrest and DNA damage inducible genes (GADDs), genes involved in cell cycle control and apoptosis, heat shock proteins, and ultimately that of genes involved in the intracellular accumulation of nonperturbing organic osmolytes. The present review summarizes the sequence of genomic responses conferring resistance against osmotic stress. In addition, the regulatory mechanisms mediating the coordinated genomic response to osmotic stress will be highlighted.

The development of microarray technology has had a significant impact on the genetic analysis of human disease. The recently developed single nucleotide polymorphism (SNP) array can be used to measure both DNA polymorphism and dosage changes. Our laboratory has applied SNP microarray analysis to uncover frequent uniparental disomies and sub-microscopic genomic copy number gains and losses in different cancers. This review will focus on the wide range of applications of SNP microarray analysis to cancer research. SNP array genotyping can determine loss of heterozygosity, genomic copy number changes and DNA methylation alterations of cancer cells. The same technology can also be used to investigate allelic association in cancers. Therefore, it can be applied to the identification of cancer predisposition genes, oncogenes and tumor suppressor genes in specific types of tumors. As a consequence, they have potential in cancer risk assessment, diagnosis, prognosis and treatment selection.

Cancer is a multi-step disease involving dynamic changes in the genome. However, studies on cancer genome so far have focused most heavily on protein-coding genes, and our knowledge on alterations of the functional noncoding sequences in cancer is largely absent. MicroRNAs (miRNAs) are endogenous small noncoding RNAs weighing 20 to 23 nucleotides that negatively regulate gene expression at the posttranscriptional level by base pairing to the 3' untranslated region of target messenger RNAs. Hundreds of miRNAs have been identified in humans and are evolutionarily conserved from plants to animals. These tiny but potent molecules regulate various physiological and pathological pathways such as cell differentiation and cell proliferation. Recently, miRNA alterations have been linked to the initiation and the progression of human cancer. As a consequence, MiRNA-expression profiling of human tumors has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify miRNA genes that might represent downstream targets of activated oncogenic pathways, or that target proteincoding genes involved in cancer. Of importance, pioneering studies described let-7 miRNA as a negative regulator of the oncogenic family of Ras guanosine triphosphatases in both Caenorhabditis elegans and human tumor cell lines. Later, let- 7 expression deregulation was reported in several cancers, suggesting that let-7 may act as a tumor suppressor. This review will discuss the late insights in let-7 function, the relationship between let-7 and tumorigenesis, and the potential for modulating let-7 expression for the treatment of cancer.

Invention of polymerase chain reaction (PCR) technology by Kary Mullis in 1984 gave birth to real-time PCR. Real-time PCR - detection and expression analysis of gene(s) in real-time - has revolutionized the 21st century biological science due to its tremendous application in quantitative genotyping, genetic variation of inter and intra organisms, early diagnosis of disease, forensic, to name a few. We comprehensively review various aspects of real-time PCR, including technological refinement and application in all scientific fields ranging from medical to environmental issues, and to plant.

The development of therapeutic resistance, after hormone or chemotherapy for example, is the underlying basis for most cancer deaths. Exposure to anticancer therapies induces expression of many stress related proteins, including small heat shock proteins (HSPs). HSPs interact with various client proteins to assist in their folding and enhance the cellular recovery from stress, thus restoring protein homeostasis and promoting cell survival. The events of cell stress and cell death are linked, as the induction of molecular chaperones appears to function at key regulatory points in the control of apoptosis. On the basis of these observations and on the role of molecular chaperones in the regulation of steroid receptors, kinases, caspases, and other protein remodelling events involved in chromosome replication and changes in cell structure, it is not surprising that molecular chaperones have been implicated in the control of cell growth and in resistance to various anticancer treatments that induce apoptosis. Recently, several molecular chaperones such as Clusterin and HSP27 have been reported to be involved in development and progression of hormone-refractory prostate cancer. In this review, we address some of the molecular and cellular events initiated by treatment induced stress, and discuss the potential role of chaperone proteins as targets for prostate cancer treatment.

The availability of sequenced genomes of human and many experimental animals necessitated the development of new technologies and powerful computational tools that are capable of exploiting these genomic data and ask intriguing questions about complex nature of biological processes. This gave impetus for developing whole genome approaches that can produce functional information of genes in the form of expression profiles and unscramble the relationships between variation in gene expression and the resulting physiological outcome. These profiles represent genetic fingerprints or catalogue of genes that characterize the cell or tissue being studied and provide a basis from which to begin an investigation of the underlying biology. Among the most powerful and versatile tools are high-density DNA microarrays to analyze the expression patterns of large numbers of genes across different tissues or within the same tissue under a variety of experimental conditions or even between species. The wide spread use of microarray technologies is generating large sets of data that is stimulating the development of better analytical tools so that functions can be predicted for novel genes. In this review, the authors discuss how these profiles are being used at various stages of the drug discovery process and help in the identification of new drug targets, predict the function of novel genes, and understand individual variability in response to drugs.