Biomedical subjects

Rebecca C Osthus

Publications and source records attributed to Rebecca C Osthus.

3 recordsLinked to original sources

PubMed2006

The c-Myc target gene network.

For more than a decade, numerous studies have suggested that the c-Myc oncogenic protein is likely to broadly influence the composition of the transcriptome. However, the evidence required to support this notion was made available only recently, much to the anticipation of an eagerly awaiting field. In the past 5 years, many high-throughput screens based on microarray gene expression profiling, serial analysis of gene expression (SAGE), chromatin immunoprecipitation (ChIP) followed by genomic array analysis, and Myc-methylase chimeric proteins have generated a wealth of information regarding Myc responsive and target genes. From these studies, the c-Myc target gene network is estimated to comprise about 15% of all genes from flies to humans. Both genomic and functional analyses of c-Myc targets suggest that while c-Myc behaves as a global regulator of transcription, groups of genes involved in cell cycle regulation, metabolism, ribosome biogenesis, protein synthesis, and mitochondrial function are over-represented in the c-Myc target gene network. c-Myc also consistently represses genes involved in cell growth arrest and cell adhesion. The overexpression of c-Myc predisposes cells to apoptosis under nutrient or growth factor deprivation conditions, although the critical sets of genes involved remain elusive. Despite tremendous advances, the downstream target genes that distinguish between physiologic and tumorigenic functions of c-Myc remain to be delineated.

Animals↗

PubMed2005

The Myc target gene JPO1/CDCA7 is frequently overexpressed in human tumors and has limited transforming activity in vivo.

MYC is frequently overexpressed in human cancers, but the downstream events contributing to tumorigenesis remain incompletely understood. MYC encodes an oncogenic transcription factor, of which target genes presumably contribute to cellular transformation. Although Myc regulates about 15% of genes and combinations of target genes are likely required for tumorigenesis, we studied in depth the expression of the Myc target gene, JPO1/CDCA7, in human cancers and its ability to provoke tumorigenesis in transgenic mice. JPO1/CDCA7 is frequently overexpressed in human cancers, and in particular, its expression is highly elevated in chronic myelogenous leukemia blast crisis as compared with the chronic phase. In murine lymphoid tissues, ectopic human JPO1/CDCA7 expression resulted in a 2-fold increased risk of lymphoid malignancies at 1 year. The transgene, which was driven by the H2-K promoter, exhibited leaky expression in nonlymphoid tissues such as kidney. We observed a significant increased incidence of transgenic animal solid tumors, which were not seen in littermate controls. These observations suggest that JPO1/CDCA7 may contribute to Myc-mediated tumorigenesis.

Alleles↗

PubMed2003

A strategy for identifying transcription factor binding sites reveals two classes of genomic c-Myc target sites.

Defining the hardwiring of transcription factors to their cognate genomic binding sites is essential for our understanding of biological processes. We used scanning chromatin immunoprecipitation to identify in vivo binding regions (E boxes) for c-Myc in three target genes as a model system. Along with other c-Myc target genes that have been validated by chromatin immunoprecipitation, we used the publicly available genomic sequences to determine whether experimentally derived in vivo binding sites might be predictable from nonexonic sequence conservation across species. Our studies revealed two classes of target genomic binding sites. Although the majority of target genes studied [class I: B23 (NPM1), CAD, CDK4, cyclin D2, ID2, LDH-A, MNT, PTMa, ODC, NM23B, nucleolin, prohibitin, SHMT1, and SHMT2] demonstrate significant sequence conservation of the E boxes and flanking regions, several genes (cyclin B1, JPO1, and PRDX3) belong to a second class (class II) that does not display sequence conservation at and around the site of c-Myc binding. On the basis of our model, we propose a strategy for predicting transcription factor binding sites using phylogenetic sequence comparisons, which will select potential class I target genes among the many emerging candidates from DNA-microarray studies for experimental validation by chromatin immunoprecipitation.

Binding Sites↗