B-ZIP transcription factors (98) are exclusively eukaryotic proteins that bind to sequence-specific double-stranded DNA as homodimers or heterodimers to either activate or repress gene transcription (34). We have examined both of the recently published DNA sequences of the human genome (51, 95) and identified 56 genes that contain the B-ZIP motif. Three sequences were identical, giving a total of 53 unique B-ZIP domains with the potential to form 2,809 dimers. This creates the possibility for a tremendous range of transcriptional control (23, 50, 52). While significant effort has been directed at identifying dimerization partners of B-ZIP proteins, the full complement of dimerization partners remains to be elucidated. This review highlights two topics: (i) the known structural rules that regulate leucine zipper dimerization specificity and (ii) experimental data addressing mammalian B-ZIP dimerization partners.We have annotated the leucine zippers of all human B-ZIP domains, highlighting amino acids in the a, d, e, and g positions that appear critical for leucine zipper dimerization specificity. These data were used to group B-ZIP proteins into 12 families with similar dimerization properties: (i) those that strongly favor homodimerization within the family (PAR, CREB, Oasis, and ATF6), (ii) those that have the ability to both homodimerize and heterodimerize with similar affinities (C/EBP, ATF4, ATF2, JUN, and the small MAFs), and (iii) those that favor heterodimerization with other families (FOS, CNC, and large MAFs). BACKGROUND

Using a mouse model recapitulating the main features of human chronic myelogenous leukemia (CML), we uncover the hierarchy of leukemic stem and progenitor cells contributing to disease pathogenesis. We refine the characterization of CML leukemic stem cells (LSCs) to the most immature long-term hematopoietic stem cells (LT-HSCs) and identify some important molecular deregulations underlying their aberrant behavior. We find that CML multipotent progenitors (MPPs) exhibit an aberrant B-lymphoid potential but are redirected towards the myeloid lineage by the action of the pro-inflammatory cytokine IL-6. We show that BCR/ABL activity controls Il-6 expression thereby establishing a paracrine feedback loop that sustains CML development. These results describe how pro-inflammatory tumor environment affects leukemic progenitor cell fate and contributes to CML pathogenesis.

We have determined the distribution of each of the 65,536 DNA sequences that are eight bases long (8-mer) in a set of 13,010 human genomic promoter sequences aligned relative to the putative transcription start site (TSS). A limited number of 8-mers have peaks in their distribution (cluster), and most cluster within 100 bp of the TSS. The 156 DNA sequences exhibiting the greatest statistically significant clustering near the TSS can be placed into nine groups of related sequences. Each group is defined by a consensus sequence, and seven of these consensus sequences are known binding sites for the transcription factors (TFs) SP1, NF-Y, ETS, CREB, TBP, USF, and NRF-1. One sequence, which we named Clus1, is not a known TF binding site. The ninth sequence group is composed of the strand-specific Kozak sequence that clusters downstream of the TSS. An examination of the co-occurrence of these TF consensus sequences indicates a positive correlation for most of them except for sequences bound by TBP (the TATA box). Human mRNA expression data from 29 tissues indicate that the ETS, NRF-1, and Clus1 sequences that cluster are predominantly found in the promoters of housekeeping genes (e.g., ribosomal genes). In contrast, TATA is more abundant in the promoters of tissue-specific genes. This analysis identified eight DNA sequences in 5082 promoters that we suggest are important for regulating gene expression.Vertebrate gene expression is often regulated by the basal promoter, which traditionally is defined as being between ‫002מ‬ bp and the transcription start site (TSS). The DNA sequence properties of basal promoters are poorly described because it is difficult to identify the TSS. Two recent results have helped to resolve this problem: (1) RefSeq Pruitt et al. 2000;Pruitt and Maglott 2001) sequences have been mapped to their location in the complete human genome sequence, and (2) TSSs have been experimentally verified for 7889 genes by using cDNA synthesis methods that identify the 5Ј CAP site (Suzuki et al. 2002). We have combined these data to assemble genomic DNA sequences that are putative promoter regions for 13,010 genes aligned relative to the putative TSS. We have examined these aligned sequences for 8-mers that are preferentially localized relative to the TSS, namely, clusters.A fundamental question in gene expression studies is to determine which DNA sequences that are bound by TFs are biologically relevant. Often, the same DNA sequence is functional in one context but not in another. We reasoned that if a DNA sequence clusters relative to the TSS, the DNA sequences that are in the cluster have a high likelihood of being biologically significant. In human promoters the CAAT box, SP1, and TATA box are recognized by the constitutive transcription factors NF-Y, SP1, and TBP, respectively, and are thought to be localized near the TSS (Breathnach and Chambon 1981). Recently, a genome-wide analysis has demonstrated that the CRE sequence clusters in human promoters (Conkright et al. 2003).To identify additional DNA sequ...

Mammalian neurogenesis is determined by an interplay between intrinsic genetic mechanisms and extrinsic cues such as growth factors. Here we have defined a signaling cascade, a MEK-C/EBP pathway, that is essential for cortical progenitor cells to become postmitotic neurons. Inhibition of MEK or of the C/EBP family of transcription factors inhibits neurogenesis while expression of a C/EBPbeta mutant that is a phosphorylation-mimic at a MEK-Rsk site enhances neurogenesis. C/EBP mediates this positive effect by direct transcriptional activation of neuron-specific genes such as Talpha1 alpha-tubulin. Conversely, inhibition of C/EBP-dependent transcription enhances CNTF-mediated generation of astrocytes from the same progenitor cells. Thus, activation of a MEK-C/EBP pathway enhances neurogenesis and inhibits gliogenesis, thereby providing a mechanism whereby growth factors can selectively bias progenitors to become neurons during development.