SummaryHutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease with widespread phenotypic features resembling premature aging. HGPS was recently shown to be caused by dominant mutations in the LMNA gene, resulting in the in-frame deletion of 50 amino acids near the carboxyl terminus of the encoded lamin A protein.Children with this disease typically succumb to myocardial infarction or stroke caused by severe atherosclerosis at an average age of 13 years. To elucidate further the molecular pathogenesis of this disease, we compared the gene expression patterns of three HGPS fibroblast cell strains heterozygous for the LMNA mutation with three normal, age-matched cell strains. We defined a set of 361 genes (1.1% of the approximately 33 000 genes analysed) that showed at least a 2-fold, statistically significant change. The most prominent categories encode transcription factors and extracellular matrix proteins, many of which are known to function in the tissues severely affected in HGPS. The most affected gene, MEOX2 /GAX , is a homeobox transcription factor implicated as a negative regulator of mesodermal tissue proliferation. Thus, at the gene expression level, HGPS shows the hallmarks of a developmental disorder affecting mesodermal and mesenchymal cell lineages. The identification of a large number of genes implicated in atherosclerosis is especially valuable, because it provides clues to pathological processes that can now be investigated in HGPS patients or animal models.

The myc proto-oncogenes encode transcriptional regulators whose inappropriate expression is correlated with a wide array of human malignancies. Up-regulation of Myc enforces growth, antagonizes cell cycle withdrawal and differentiation, and in some situations promotes apoptosis. How these phenotypes are elicited is not well understood, largely because we lack a clear picture of the biologically relevant downstream effectors. We created a new biological system for the optimal profiling of Myc target genes based on a set of isogenic c-myc knockout and conditional cell lines. The ability to modulate Myc activity from essentially null to supraphysiological resulted in a significantly increased and reproducible yield of targets and revealed a large subset of genes that respond optimally to Myc in its physiological range of expression. The total extent of transcriptional changes that can be triggered by Myc is remarkable and involves thousands of genes. Although the majority of these effects are not direct, many of the indirect targets are likely to have important roles in mediating the elicited cellular phenotypes. Myc-activated functions are indicative of a physiological state geared toward the rapid utilization of carbon sources, the biosynthesis of precursors for macromolecular synthesis, and the accumulation of cellular mass. In contrast, the majority of Myc-repressed genes are involved in the interaction and communication of cells with their external environment, and several are known to possess antiproliferative or antimetastatic properties.The Myc protein is a member of the basic region/helix-loophelix/leucine zipper (b/HLH/Zip) family of transcriptional regulators and is capable of exerting both transactivation and transrepression activities (1, 2). Transactivation is mediated by binding as an obligate heterodimer with the b/HLH/Zip factor Max to the consensus sequence CA(C/T)GTG (the E box) (3). Transrepression is less well understood (4, 5). In either mode Myc is a weak transcriptional regulator, exerting most of its effects within the 2-5-fold range. In a general sense, the upregulation of Myc strongly enforces proliferation and growth, antagonizes cell cycle withdrawal and differentiation, and in some situations promotes apoptosis (6 -8). In agreement, the down-regulation of Myc results in the attenuation of both cell division and cell growth as well as protection against some apoptotic processes (9 -13). Despite extensive research, the specific mechanisms by which these highly evident biological end points are achieved are not well understood. This is largely because a comprehensive list of biologically relevant Myc target genes has not yet been defined.A wide variety of techniques have been employed in the hunt for Myc targets, ranging from differential expression screens, promoter analysis, and informed guesswork (14 -16) to the modern methods of microarray profiling, serial analysis of gene expression, and chromatin immunoprecipitation (17-23). This search has been complicated by several factors. Firs...

CD18 (␤ 2 leukocyte integrin) is a leukocyte-specific adhesion molecule that plays a crucial role in immune and inflammatory responses. A 79-nucleotide fragment of the CD18 promoter is sufficient to direct myeloid transcription. The CD18 promoter is bound by the B lymphocyte-and myeloid-restricted ets factor, PU.1, and disruption of the PU.1-binding sites significantly reduces promoter activity. However, PU.1 alone cannot fully account for the leukocyte-specific and myeloid-inducible transcription of CD18. We identified a ubiquitously expressed nuclear protein complex of extremely low electrophoretic mobility that also binds to this region of the CD18 promoter. This binding complex is a heterotetramer composed of GABP␣, an ets factor, and GABP␤, a subunit with homology to Drosophila Notch. GABP␣ competes with the lineage restricted factor, PU.1, for the same critical CD18 ets sites. The CD18 promoter is activated in myeloid cells by transfection with both GABP␣ and GABP␤ together, but not by either factor alone. Transfection of non-hematopoietic cells with the two GABP subunits together with PU