Gene expression levels of about 7,000 genes were measured in 11 different human adult and fetal tissues using high-density oligonucleotide arrays to identify genes involved in cellular maintenance. The tissues share a set of 535 transcripts that are turned on early in fetal development and stay on throughout adulthood. Because our goal was to identify genes that are involved in maintaining cellular function in normal individuals, we minimized the effect of individual variation by screening mRNA pooled from many individuals. This information is useful for establishing average expression levels in normal individuals. Additionally, we identified transcripts uniquely expressed in each of the 11 tissues.

This study creates a compendium of gene expression in normal human tissues suitable as a reference for defining basic organ systems biology. Using oligonucleotide microarrays, we analyze 59 samples representing 19 distinct tissue types. Of ∼7,000 genes analyzed, 451 genes are expressed in all tissue types and designated as housekeeping genes. These genes display significant variation in expression levels among tissues and are sufficient for discerning tissue-specific expression signatures, indicative of fundamental differences in biochemical processes. In addition, subsets of tissue-selective genes are identified that define key biological processes characterizing each organ. This compendium highlights similarities and differences among organ systems and different individuals and also provides a publicly available resource (Human Gene Expression Index, the HuGE Index, http://www.hugeindex.org ) for future studies of pathophysiology.

Quiescent mouse embryonic C3H͞10T 1 ⁄2 cells are more resistant to different proapoptotic stimuli than are these cells in the exponential phase of growth. However, the exponentially growing 10T 1 ⁄2 cells are resistant to inhibitors of RNA or protein synthesis, whereas quiescent cells die upon these treatments. Conditioned medium from quiescent 10T 1 ⁄2 cells possesses anti-apoptotic activity, suggesting the presence of protein(s) that function as an inhibitor of the apoptotic program. Using differential display technique, we identified and cloned a cDNA designated sarp1 (secreted apoptosis-related protein) that is expressed in quiescent but not in exponentially growing 10T 1 ⁄2 cells. Hybridization studies with sarp1 revealed two additional family members. Cloning and sequencing of sarp2 and sarp3 revealed 38% and 40% sequence identity to sarp1, respectively. Human breast adenocarcinoma MCF7 cells stably transfected with sarp1 or infected with SARP1-expressing adenovirus became more resistant, whereas cells transfected with sarp2 displayed increased sensitivity to different proapoptotic stimuli. Expression of sarp family members is tissue specific. sarp mRNAs encode secreted proteins that possess a cysteine-rich domain (CRD) homologous to the CRD of frizzled proteins but lack putative membrane-spanning segments. Expression of SARPs modifies the intracellular levels of ␤-catenin, suggesting that SARPs interfere with the Wnt-frizzled proteins signaling pathway.

Loss of function of BRCA1 caused by inherited mutation and tissuespecific somatic mutation leads to breast and ovarian cancer. Nearly all BRCA1 germ-line mutations involve truncation or loss of the C-terminal BRCT transcriptional activation domain, suggesting that transcriptional regulation is a critical function of the wild-type gene. The purpose of this project was to determine whether there is a link between the role of BRCA1 in transcriptional regulation and its role in tumor suppression. We developed a cell line (in which BRCA1 can be induced) and used microarray analysis to compare transcription profiles of epithelial cells with low endogenous levels of BRCA1 vs. transcription profiles of cells with 2-4-fold higher induced levels of expression of BRCA1. At these levels of expression, BRCA1 did not induce apoptosis. Undirected cluster analysis of six paired experiments revealed 373 genes, the expression of which was altered significantly and consistently by BRCA1 induction. Expression of 62 genes was altered more than 2-fold. BRCA1-regulated genes associated with breast tumorigenesis included the estrogen-responsive genes MYC and cyclin D1, which are overexpressed in many breast tumors; STAT1 and JAK1, key components of the cytokine signal transduction pathway; the extracellular matrix protein laminin 3A; ID4, an inhibitor of DNA-binding transcriptional activators, which in turn negatively regulates BRCA1 expression; and the prohormone stanniocalcin, expression of which is lost in breast tumor cells. Coordinated expression of BRCA1 with ID4 and with stanniocalcin was confirmed in primary breast and ovarian tumors.B RCA1 is a tumor-suppressor gene in which germ-line mutations predispose to breast and ovarian cancer (1, 2). Tumorigenesis in individuals with germ-line BRCA1 mutations requires somatic inactivation of the remaining wild-type allele (3). In breast and ovarian tumors of patients with no BRCA1 germ-line mutation, expression of BRCA1 is reduced also (4-6). BRCA1 null cells are severely aneuploid with unstable karyotypes (7). BRCA1 regulates multiple nuclear processes including DNA repair and recombination, checkpoint control of the cell cycle, and transcription (reviewed in ref. 8). Much of the evidence for involvement of BRCA1 in these processes is based on identification of multiprotein complexes in which BRCA1 is found. BRCA1 associates with RAD51 and BRCA2 in nuclear foci induced by ionizing radiation (9, 10). RAD 51 catalyzes strand exchange during homology-directed repair of DNA double-strand breaks by gene conversion, suggesting a role for BRCA1 in DNA repair by homologous recombination. BRCA1 also associates directly with the MRE11-RAD50-NBS1 complex, which is responsible for end-processing of double-strand breaks (11,12). In addition, BRCA1 is involved in the repair of oxidative DNA damage by transcription-coupled repair (13,14). BRCA1 is found in two large complexes involved in DNA repair and chromatin remodeling. BRCA1 is a component of BASC, a BRCA1-associated genome surveillance complex...

Large scale gene expression pro®ling was carried out on laser capture microdissected (LCM) tumor and normal oral epithelial cells and analysed on high-density oligonucleotide microarrays. About 600 genes were found to be oral cancer associated. These oral cancer associated genes include oncogenes, tumor suppressors, transcription factors, xenobiotic enzymes, metastatic proteins, di erentiation markers, and genes that have not been implicated in oral cancer. The database created provides a veri®able global pro®le of gene expression during oral carcinogenesis, revealing the potential role of known genes as well as genes that have not been previously implicated in oral cancer. Oncogene (2001) 20, 6196 ± 6204.