Biomedical subjects

J E Landers

Publications and source records attributed to J E Landers.

5 recordsLinked to original sources

PubMed2006

Using high-throughput SNP technologies to study cancer.

Identifying genes involved in the development of cancer is crucial to fully understanding cancer biology, for developing novel therapeutics for cancer treatment and for providing methods for cancer prevention and early diagnosis. The use of polymorphic markers, in particular single nucleotide polymorphisms (SNPs), promises to provide a comprehensive tool for analysing the human genome and identifying those genes and genomic regions contributing to the cancer phenotype. This review summarizes the various analytical methodologies in which SNPs are used and presents examples of how each of these methodologies have been used to locate genes and genomic regions of interest for various cancer types. Additionally many of the current SNP-analysing technologies will be reviewed with particular attention paid to the advantages and disadvantages of each and how each technology can be applied to the analysis of the genome for identifying cancer-related genes.

Genetic Linkage↗

PubMed1997

Translational enhancement of mdm2 oncogene expression in human tumor cells containing a stabilized wild-type p53 protein.

The mdm2 oncogene has transforming potential that is activated by overexpression. We previously reported the identification of human choriocarcinoma cell lines that have very high levels of mdm2 proteins as well as elevated levels of a stabilized wild-type p53 protein. Importantly, this mdm2 overexpression resulted from enhanced translation of mdm2 mRNA, a mechanism that had not previously been implicated in mdm2 expression control. The focus of this study was to investigate the breadth of enhanced translation of mdm2 mRNA in human cancers and to elucidate the basis for this translational activation. Here we present evidence that translational enhancement of mdm2 expression occurs in a variety of human tumor cells. Most of these samples also have high levels of wild-type p53 protein. However, there is no evidence for concomitant overexpression of the p53 target genes p21/waf1 and gadd45. Additionally, we demonstrate that the translational enhancement of mdm2 involves a preferential increase in mdm2 transcription that is initiated from the internal p53-responsive promoter region of this gene. The particular mdm2 transcripts that are generated contain a distinct 5' untranslated region and exhibit a significantly enhanced translational efficiency. These data provide a quantitative explanation for the overexpression of mdm2 proteins in this class of human tumors.

Base Sequence↗

PubMed1994

Physical and functional interaction between wild-type p53 and mdm2 proteins.

The mdm2 oncogene, which is often amplified in mammalian tumors, produces a number of transcripts that encode distinct protein forms. Previous studies demonstrating that overexpression of the mdm2 gene can activate its transforming potential, and can inhibit the transcriptional activation function of p53, prompted us to begin to explore possible functional differences among the various mdm2 products. Utilizing a transient transfection assay, we have evaluated four naturally occurring murine mdm2 forms for their ability to inhibit p53-mediated transcriptional activation of reporter genes regulated by p53 response elements. Three of these mdm2 forms were found to physically associate with the wild-type p53 protein and to possess the ability to inhibit its transactivation function. A fourth form failed to exhibit either of these functions. This last mdm2 form lacks the N-terminal protein domain that is present in the other three splice forms examined, pointing to this region as one that is critical for complex formation with the p53 protein. Identifying such differences among mdm2 proteins provides important clues for dissecting their functional domains, and emphasizes that defining the individual properties of these products will be critical in elucidating the overall growth control function of the mdm2 gene.

Alternative Splicing↗

PubMed1994

Enhanced translation: a novel mechanism of mdm2 oncogene overexpression identified in human tumor cells.

The cellular mdm2 gene, which has potential transforming activity that can be activated by overexpression, is amplified in a significant percentage of human sarcomas and in other mammalian tumors. Proteins encoded by the mdm2 gene can bind to, and inhibit the function of, the protein product of the p53 tumor suppressor gene. As reported here, we have identified human choriocarcinoma cell lines that express high levels of mdm2 proteins as well as the p53 protein. Several lines of evidence demonstrate that the p53 in these tumor cells has a wild-type nucleotide sequence, although the protein exhibits an extended half-life. Further, the more than 100-fold overexpression of mdm2 proteins in these cells cannot be explained by gene amplification, elevated RNA expression, or altered protein stability; rather our data indicate that elevated mdm2 protein levels in these choriocarcinoma cell lines result from enhanced translation. This mechanism has not previously been implicated in the regulation of mdm2 gene expression, and it represents a novel means by which the potential transforming activity of the mdm2 oncogene could be activated.

Base Sequence↗

PubMed1992

Isolation of a candidate gene for choroideremia.

Choroideremia is an X chromosome-linked retinal dystrophy of unknown pathogenesis. We have isolated cDNAs from a human retinal library with a genomic probe located at the X chromosomal breakpoint in a female with choroideremia and an X;13 translocation. This cDNA spans the breakpoint in the X;13 translocation female and is deleted in males who have choroideremia as part of a complex phenotype including mental retardation and deafness. However, this cDNA detects no alterations in the DNA of 34 males with isolated choroideremia. Nonetheless, the cDNA does detect reduced or absent levels of mRNA in three-quarters of male patients with an apparently intact gene. These data support the hypothesis that this cDNA represents the gene in which mutations cause choroideremia.

Amino Acid Sequence↗