Genomic and expression profiling of glioblastoma stem cell-like spheroid cultures identifies novel tumor-relevant genes associated with survival.

Purpose: Glioblastoma spheroid cultures are enriched in tumor stem-like cells and therefore may be more representative of the respective primary tumors than conventional monolayer cultures. We exploited the glioma spheroid culture model to find novel tumor-relevant genes.

Experimental Design: We carried out array-based comparative genomic hybridization of spheroid cultures derived from 20 glioblastomas.

The transcription factor Fos: a Janus-type regulator in health and disease.

The immediate early gene product Fos is part of the activator protein-1 (AP-1) transcription factor and has been shown to participate in the molecular mechanisms of cell proliferation, differentiation, apoptosis, and transformation. The analysis of genetically modified mice and cells derived thereof has provided important new insights into its specific biological functions in development, tissue homeostasis, and cellular responses to environmental insults. Moreover, the deregulation of Fos could be linked with a variety of pathological conditions, including immunological, skeletal and neurological defects, as well as oncogenic transformation and tumor progression.

Podoplanin is a novel fos target gene in skin carcinogenesis.

Expression and function of the oncogenic transcription factor activator protein (AP-1; mainly composed of Jun and Fos proteins) is required for neoplastic transformation of keratinocytes in vitro and tumor promotion as well as malignant progression in vivo. Here, we describe the identification of 372 differentially expressed genes comparing skin tumor samples of K5-SOS-F transgenic mice (Fos(f/f) SOS(+)) with samples derived from animals with a specific deletion of c-Fos in keratinocytes (Fos(Deltaep) SOS(+)). Fos-dependent transcription of selected genes was confirmed by quantitative real-time PCR analysis using tumor samples and mouse back skin treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA).

RAGE signaling sustains inflammation and promotes tumor development.

A broad range of experimental and clinical evidence has highlighted the central role of chronic inflammation in promoting tumor development. However, the molecular mechanisms converting a transient inflammatory tissue reaction into a tumor-promoting microenvironment remain largely elusive. We show that mice deficient for the receptor for advanced glycation end-products (RAGE) are resistant to DMBA/TPA-induced skin carcinogenesis and exhibit a severe defect in sustaining inflammation during the promotion phase.

Oxidant-induced cell-cycle delay in Saccharomyces cerevisiae: the involvement of the SWI6 transcription factor.

Cells treated with low doses of linoleic acid hydroperoxide (LoaOOH) exhibit a cell-cycle delay that may provide a mechanism to overcome oxidative stress. Strains sensitive to LoaOOH from the genome-wide deletion collection were screened to identify deletants in which the cell-cycle delay phenotype was reduced. Forty-seven deletants were identified that were unable to mount the normal delay response, implicating the product of the deleted gene in the oxidant-mediated cell-cycle delay of the wild-type.

Electrophilic chemicals but not UV irradiation or reactive oxygen species activate Nrf2 in keratinocytes in vitro and in vivo.

The NF-E2-related factor 2 (Nrf2) transcription factor is a potent inducer of cytoprotective genes, which encode--among others--enzymes that detoxify reactive oxygen species (ROS). As we demonstrated a crucial role of Nrf2 in the prevention of skin carcinogenesis, it is of interest to identify Nrf2-activating factors in keratinocytes. For this purpose, keratinocytes from mice transgenic for an Nrf2-responsive reporter gene were analyzed.