Biomedical subjects

Lewis A Chodosh

Publications and source records attributed to Lewis A Chodosh.

42 records · Page 3Linked to original sources

PubMed2002

Gene expression profiling of HeLa cells in G1 or G2 phases.

The cell division cycle is regulated through both transcriptional and post-transcriptional mechanisms. The altered expression of a number of genes at the mRNA level is known to be essential for progression through the cell cycle, however, a comprehensive gene expression profile of human cells remains to be completed. Here we sought to monitor the differential gene expression of genes after the transition of G2 cells into G1 prior to the restriction point. GeneChip containing microarrays of oligonucleotides corresponding to over 12 000 human genes were employed to profile differential gene expression in G1 and G2. After three independent experiments the resultant data was filtered and a set of genes was compiled based on at least threefold-altered expression, no background noise in determining expression and observation in all experiments. Our analysis identified 154 genes that were elevated in G2 phase of cells as compared to early G1 phase including 15 novel genes. This number included mRNAs whose upregulation is known to occur in G2 phase. Surprisingly only 19 genes were upregulated in G1 phase, among these six genes were novel. Some of these genes are candidates for transition through early G1. This gene inventory for G1 and G2 phases of cell cycle will provide the basis for understanding of cell cycle delay as a result of DNA damage.

Blotting, Northern↗

PubMed2002

Genomic scale profiling of autoimmune inflammation in the central nervous system: the nervous response to inflammation.

Using gene microarray technology, we found that inflammation in the central nervous system (CNS) not only induced the expression of many immune-related genes, but also significantly altered the gene expression profile of neural cells. Two unique groups of CNS genes were identified. The first group includes genes encoding ion channels, neural transmitters and growth factors. The second group includes genes that are important for nervous tissue regeneration. Additionally, a distinct pattern of gene expression was also identified in recovering animals. Thus, during autoimmune inflammation, the CNS actively responds to immune attacks by activating its own defense and repair genes.

Animals↗

PubMed2002

Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis.

To determine the impact of tumor progression on the reversibility of Neu-induced tumorigenesis, we have used the tetracycline regulatory system to conditionally express activated Neu in the mammary epithelium of transgenic mice. When induced with doxycycline, bitransgenic MMTV-rtTA/TetO-NeuNT mice develop multiple invasive mammary carcinomas, essentially all of which regress to a clinically undetectable state following transgene deinduction. This demonstrates that Neu-initiated tumorigenesis is reversible. Strikingly, extensive lung metastases arising from Neu-induced mammary tumors also rapidly and fully regress following the abrogation of Neu expression. However, despite the near universal dependence of both primary tumors and metastases on Neu transgene expression, most animals bearing fully regressed Neu-induced tumors ultimately develop recurrent tumors that have progressed to a Neu-independent state.

Adenocarcinoma↗

PubMed2002

A novel doxycycline-inducible system for the transgenic analysis of mammary gland biology.

Normal developmental events such as puberty, pregnancy, and parity influence the susceptibility of the mammary gland to tumorigenesis in both humans and rodent model systems. Unfortunately, constitutive transgenic mouse models that rely on mammary-specific promoters to control transgene expression have limited utility for studying the effect of developmental events on breast cancer risk since the hormonal signals governing these events also markedly influence transgene expression levels. A novel transgenic mouse system is described that uses the MMTV-LTR to drive expression of the reverse tetracycline-dependent transactivator rtTA. Transgenic mice expressing rtTA in the mammary epithelium were crossed with reporter lines bearing tet operator-controlled transgenes. We tested the ability to spatially, temporally, and quantitatively control reporter gene expression after administration of doxycycline to bitransgenic mice. Transgene expression using this system can be rapidly induced and deinduced, is highly mammary specific, can be reproducibly titrated over a wide range of expression levels, and is essentially undetectable in the uninduced state. Homogeneous transgene expression throughout the mammary epithelium can be achieved. This system permits transgene expression to be restricted to any desired stage of postnatal mammary gland development. We have developed a mammary-specific, doxycycline-inducible transgenic mouse model for studying the effect of mammary gland development on transgene-mediated phenotypes. Unlike other mammary-specific, transgenic systems that have been described, this system combines spatially homogeneous transgene expression in the mammary epithelium during puberty, pregnancy, lactation, and involution with the use of an orally administered, inexpensive, and widely available inducing agent. This system offers new opportunities for the transgenic analysis of mammary gland biology in vivo.

Animals↗

PubMed2002

Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland.

Epidemiological studies have repeatedly demonstrated that women who undergo an early first full-term pregnancy have a significantly reduced lifetime risk of breast cancer. Similarly, rodents that have previously undergone a full-term pregnancy are highly resistant to carcinogen-induced breast cancer compared with age-matched nulliparous controls. Little progress has been made, however, toward understanding the biological basis of this phenomenon. We have used DNA microarrays to identify a panel of 38 differentially expressed genes that reproducibly distinguishes, in a blinded manner, between the nulliparous and parous states of the mammary gland in multiple strains of mice and rats. We find that parity results in the persistent down-regulation of multiple genes encoding growth factors, such as amphiregulin, pleiotrophin, and IGF-1, as well as the persistent up-regulation of the growth-inhibitory molecule, TGF-beta3, and several of its transcriptional targets. Our studies further indicate that parity results in a persistent increase in the differentiated state of the mammary gland as well as lifelong changes in the hematopoietic cell types resident within the gland. These findings define a developmental state of the mammary gland that is refractory to carcinogenesis and suggest novel hypotheses for the mechanisms by which parity may modulate breast cancer risk.

Animals↗

PubMed2002

Functional microarray analysis of mammary organogenesis reveals a developmental role in adaptive thermogenesis.

The use of DNA microarrays to study vertebrate organogenesis presents unique analytical challenges compared with expression profiling of homogeneous cell populations. We have used a general approach that permits the automated, unbiased identification of biologically relevant patterns of gene expression to study murine mammary gland development. Our studies confirm the utility of this approach by demonstrating the ready identification of cellular processes and pathways of known functional importance in mammary development. Additionally, this approach permitted the identification of genetic pathways with unpredicted patterns of developmental regulation, including those involved in angiogenesis, extracellular matrix synthesis, and the beta-oxidation of fatty acids. Surprisingly, our findings demonstrate that the coordinate regulation of genes involved in the beta-oxidation of fatty acids reflects the presence of an abundant, yet previously unrecognized stromal compartment within the mammary gland that is composed of brown adipose tissue. Our data demonstrate that the amount of brown adipose tissue present in the mammary gland is developmentally regulated; that PPARalpha, Ucp1, and genes involved in fatty acid oxidation are spatially and temporally coregulated during development; that the mammary gland plays a functional role in adaptive thermogenesis; and that the transcriptional control of this adaptive response to cold is itself developmentally regulated.

Adipose Tissue, Brown↗