Biomedical subjects

Patrick Onyango

Publications and source records attributed to Patrick Onyango.

6 recordsLinked to original sources

PubMed2004

The role of emerging genomics and proteomics technologies in cancer drug target discovery.

Cancer drugs have traditionally been identified in screens designed to produce broad biological end points such as cell death. A serious undesired outcome of drugs discovered in these screens is that the mechanism of drug action is unknown and such drugs often have adverse side effects. Designing cancer drugs that act on specific targets offer the advantage that the mechanism of drug action can be understood and accurately monitored in clinical trials leading to development of better drugs. The pharmacological industry has recently shifted to a target directed drug discovery model. However, until recently potential cancer drug targets comprised of only a small fraction of the human genome. The human genome project and high-throughput structural and functional genomics have dramatically increased the number of cancer drug targets. Deciphering cancer drug targets requires the understanding of biochemical pathways that are affected in the cancer genome. It has been suggested that utilization of Single-nucleotide polymorphisms (SNPs) will aid in identifying individuals at high risk of developing certain cancers, and will also help in development of tailored medication or identify genetic profiles of specific drug action and toxicity. Achieving successful new cancer drug development schemes will require a merger of research disciplines that include pharmacology, genomics, comparative genomics, functional genomics, proteomics and bioinformatics. In this review the significance and challenges of these rapidly evolving technologies in cancer drug target discovery are discussed.

Animals↗

PubMed2003

Oncogenomics: prospects for the future.

Genomics has generated a wealth of data that is now being used to identify additional molecular alterations associated with cancer development. Mapping these alterations in the cancer genome is a critical first step in dissecting oncological pathways. There are two ways in which cancer research has changed in recent years. The first is the progressive elucidation of the genomic basis of cancer. This has been accomplished by the generation of detailed information using procedures such as global expression profiling. The second is a renewed emphasis on the role of epigenetic modifications in the etiology of cancer. Changes in DNA methylation and chromatin modification patterns are some of the epigenetic factors that cause gene deregulation in cancer. In this article, current and evolving genomic applications and the hypotheses underlying the modality for cancer therapy will be reviewed.

Animals↗

PubMed2002

Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2.

Epigenetic alterations in human cancers include global DNA hypomethylation,gene hypomethylation and promoter hypermethylation, and loss of imprinting (LOI) of the insulin-like growth factor-II gene (IGF2). A mechanism for LOI described previously is hypermethylation of a differentially methylated region (DMR) upstream of the H19 gene, allowing activation of the normally silent maternal allele of IGF2. Here we show that this mechanism does not apply to colorectal cancers, which show hypomethylation of the H19 DMR as well as a DMR upstream of exon 3 of IGF2. This hypomethylation is found in both colorectal cancers and normal mucosa from the same patients, and in cell lines with somatic cell knockout of DNA methyltransferases DNMT1 and DNMT3B. These data suggest that hypomethylation is a mechanism for LOI, that the popular IGF2-H19 enhancer competition model for IGF2 imprinting does not apply to the human colon, and that an alternative model for LOI would involve a transcriptional repressor acting on the normally silent maternal allele of IGF2.

Colorectal Neoplasms↗

PubMed2002

SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria.

The SIR2 (silent information regulator 2) gene family has diverse functions in yeast including gene silencing, DNA repair, cell-cycle progression, and chromosome fidelity in meiosis and aging. Human homologues, termed sirtuins, are highly conserved but are of unknown function. We previously identified a large imprinted gene domain on 11p15.5 and investigated the 11p15.5 sirtuin SIRT3. Although this gene was not imprinted, we found that it is localized to mitochondria, with a mitochondrial targeting signal within a unique N-terminal peptide sequence. The encoded protein was found also to possess NAD(+)-dependent histone deacetylase activity. These results suggest a previously unrecognized organelle for sirtuin function and that the role of SIRT3 in mitochondria involves protein deacetylation.

Amino Acid Sequence↗

PubMed2002

Monoallelic expression and methylation of imprinted genes in human and mouse embryonic germ cell lineages.

Imprinting is an epigenetic modification leading to monoallelic expression of some genes, and disrupted imprinting is believed to be a barrier to human stem cell transplantation, based on studies that suggest that epigenetic marks are unstable in mouse embryonic germ (EG) and embryonic stem (ES) cells. However, stem cell imprinting has not previously been examined directly in humans. We found that three imprinted genes, TSSC5, H19, and SNRPN, show monoallelic expression in in vitro differentiated human EG-derived cells, and a fourth gene, IGF2, shows partially relaxed imprinting at a ratio from 4:1 to 5:1, comparable to that found in normal somatic cells. In addition, we found normal methylation of an imprinting control region (ICR) that regulates H19 and IGF2 imprinting, suggesting that imprinting may not be a significant epigenetic barrier to human EG cell transplantation. Finally, we were able to construct an in vitro mouse model of genomic imprinting, by generating EG cells from 8.5-day embryos of an interspecific cross, in which undifferentiated cells show biallelic expression and acquire preferential parental allele expression after differentiation. This model should allow experimental manipulation of epigenetic modifications of cultured EG cells that may not be possible in human stem cell studies.

Alleles↗

PubMed2002

Genomics and cancer.

Genetic and environmental factors are responsible for the genomic lesions that cause cancer, a complex genetic disease associated with genomic instability. Studies aimed at deciphering the lesions in cancer have focused mainly on one or a few genes, despite the genomic scope of the disease. The recently decoded human DNA sequence is anticipated to foster understanding of human evolution and disease and the role of environment and heredity in the human condition. This review addresses the opportunities and challenges that the availability of the human genome sequence holds for cancer research.

Genetic Therapy↗