Kegg Pathway: Basal transcription factors

Am J Physiol Heart Circ Physiol. 2008 Jul 18;
Fang CX, Dong F, Thomas DP, Ma H, He L, Ren J

Cellular hypertrophy is regulated by coordinated pro- and antigrowth machineries. Foxo transcription factors initiate an atrophy-related gene program to counter hypertrophic growth. This study was designed to evaluate the role of Akt, forkhead transcription factor Foxo3a, and atrophy genes MuRF1 and Atrogin-1, in cardiac hypertrophy and contractile dysfunction associated with high fat diet-induced obesity. Mice were fed a low or high fat diet for 6 months along with a food-restricted high fat weight control group. Echocardiography revealed decreased fractional shortening, increased end systolic diameter and cardiac hypertrophy in high fat obese but not the weight control mice. Cardiomyocytes from high fat obese but not weight control mice displayed contractile and intracellular Ca(2+) defects including depressed maximal velocity of shortening/ relengthening, prolonged duration of shortening/relengthening, reduced intracellular Ca(2+) rise and clearance. Caspase activities were greater in high fat obese but not weight control mouse hearts. Western blot analysis revealed enhanced Basal Akt and Foxo3a phosphorylation, reduced insulin-stimulated phosphorylation of Akt and Foxo3a without changes in total protein expression of Akt and Foxo3a in high fat obese hearts. RT-PCR and immunoblotting results displayed reduced levels of atrogens atrogin-1 and MuRF1, upregulated hypertrophic markers GATA4 and CTNFRalpha as well as unchanged calcineurin and proteasome ubiquitin in high fat obese mouse hearts. Transfection of H9C2 myoblast cells with dominant negative (DN) Foxo3a adenovirus mimicked palmitic acid (0.8 mM for 24 hrs)-induced GATA4 upregulation without additive effect. DN Foxo3a-induced upregulation of pAkt and repression of PTEN was abrogated by palmitic acid. These results suggest cardiac hypertrophic response in high fat diet-associated obesity at least in part through inactivation of Foxo3a by Akt pathway. Key words: high fat, hypertrophy, myocardial function, foxo.

Gene. 2008 Jun 21;
Teng H, Parker MI, Prince S

Tbx2, a member of the T-box family of genes that encode developmentally important transcription factors, plays a critical role in development and has been linked to cancer. Here a 5'-flanking region of the human Tbx2 gene was cloned and characterized. While we identify a Sp1 element and a reverse CCAAT box to be essential for Basal Tbx2 promoter activity, a physical interaction between Sp1 and NF-Y does not seem to be required for mediating their effect. Furthermore, our data reveal a downstream promoter element (DPE) in the Tbx2 promoter which significantly influences Basal activity.

Am J Respir Cell Mol Biol. 2008 Jul 10;
Mercer BA, Wallace AM, Brinckerhoff CE, D'Armiento JM

Rationale: Tobacco-related diseases are leading causes of death worldwide, and many are associated with expression of matrix metalloproteinase-1 (MMP-1). We have reported ERK1/2-dependent induction of MMP-1 by cigarette smoke in lung epithelial cells. Objectives: Define regions of the human MMP-1 promoter required for activation by smoke, identify differences in responses of the 1G/2G -1607 polymorphic promoters to smoke, and identify relevant transcription factors whose activity in airway epithelial cells is increased by smoke. Methods: Responses of deletion and mutant promoter constructs were measured in transfected cells during exposure to cigarette smoke extract (CSE). DNA oligonucleotide arrays were used to identify transcription factors activated following smoke exposure. Results: CSE activated the MMP-1 promoter, and this induction was prevented by PD98059 blockade of ERK1/2 phosphorylation. Deletion studies revealed the distal 1kb promoter region (-4438 to -3280 upstream of the transcription start site) is essential for CSE induction of MMP-1, and confers activation of a minimal promoter. Studies of 1G and 2G MMP-1 polymorphic promoter variants revealed higher 2G allele Basal and CSE-responsive activities than the 1G allele. Cotransfection, mithramycin, and EMSA studies identified activating and repressive roles for Sp1 and PEA3 transcription factors, respectively. Oligonucleotide DNA arrays confirmed activation of Sp1 and PEA3 by CSE. Conclusions: These data demonstrate that the MMP-1 promoter is a direct target of cigarette smoke in lung epithelial cells. This characterization of a smoke response region in the distal MMP-1 promoter has implications for smoking-related diseases like cancer, heart disease, and emphysema.

Int J Obes (Lond). 2008 Jul 8;
Pettersson AT, Laurencikiene J, Nordström EA, Stenson BM, van Harmelen V, Murphy C, Dahlman I, Rydén M

Background:Cell death-inducing DFFA (DNA fragmentation factor-alpha)-like effector A (CIDEA) is a protein that regulates lipolysis in human adipocytes through cross-talk involving tumor necrosis factor-alpha (TNF-alpha). TNF-alpha downregulates CIDEA mRNA although it is unclear whether this is mediated through transcriptional or post-transcriptional mechanisms. CIDEA has important metabolic effects in human fat cells and genetic variations in the human CIDEA gene have been correlated to the development of obesity. However, little is known about the factors regulating CIDEA expression in human adipocytes. We set out to describe the transcriptional control of human CIDEA.Methods:A 1.1-kb genomic fragment upstream of the transcriptional start site (TSS) of human CIDEA was cloned and deletion fragments were generated. transcriptional activity of the promoter was analyzed by luciferase reporter assays in in vitro-differentiated human adipocytes. The effect of TNF-alpha was assessed in human adipocytes and murine 3T3-L1 cells transfected with deletion fragments of the CIDEA promoter. Protein-DNA interactions were analyzed by electrophoretic mobility shift assays (EMSA).Results:Basal transcriptional activity was found in a 97-bp region upstream of the TSS. We studied the effect of three common haplotypes in the promoter region but found no significant difference in transcriptional activity among them. Incubation of in vitro-differentiated human adipocytes as well as 3T3-L1 cells with TNF-alpha reduced the transcriptional activity of the human CIDEA promoter, demonstrating a direct effect on CIDEA transcription. EMSAs and mutational analysis indicated that this was mediated by a nuclear factor-kappaB (NF-kappaB) site at position -163/-151.Conclusion:We demonstrate that Basal transcription of the human CIDEA gene is confined to the 97 first bases upstream of TSS and that TNF-alpha negatively regulates transcription of this gene, which at least in part involves NF-kappaB activation.International Journal of Obesity advance online publication, 8 July 2008; doi:10.1038/ijo.2008.101.

Eur J Immunol. 2008 Jul 4;
Mora-López F, Pedreño-Horrillo N, Delgado-Pérez L, Brieva JA, Campos-Caro A

The positive regulatory domain containing 1, encoded by the PRDM1 gene, is a transcriptional repressor considered as a master regulator that is required and sufficient for plasma cell differentiation. In the present study we have performed sequence analysis of the upstream region of the human PRDM1 gene to detect the minimal promoter region necessary for PRDM1 gene transcription. This region comprises the region upstream of the initiation site, as well as the first exon. Collectively, deletion and mutation analysis in conjunction with luciferase reporter assays, EMSA and supershift assays identified a phylogenetically conserved GC-box as an essential element for PRDM1 expression. This GC-box element matches to a binding site for multiple transcription factors such as SP1 and SP3 isoforms as well as early growth response 1. Chromatin immunoprecipitation assays confirmed the in vivo binding capability of these factors to the human PRDM1 promoter. These studies together characterize for the first time the Basal activity of the human PRDM1 promoter, through which several factors, including SP1, SP3 and early growth response 1, modulate its expression through a conserved GC-box.

FASEB J. 2008 Jul 2;
Dobrosi N, Tóth BI, Nagy G, Dózsa A, Géczy T, Nagy L, Zouboulis CC, Paus R, Kovács L, Bíró T

We had previously shown that both locally produced endocannabinoids and exocannabinoids, via cannabinoid receptor-1 (CB1), are powerful inhibitors of human hair growth. To further investigate the role of the cannabinoid system in pilosebaceous unit biology, we have explored in the current study whether and how endocannabinoids have an impact on human sebaceous gland biology, using human SZ95 sebocytes as cell culture model. Here, we provide the first evidence that SZ95 sebocytes express CB2 but not CB1. Also, prototypic endocannabinoids (arachidonoyl ethanolamide/anandamide, 2-arachidonoyl glycerol) are present in SZ95 sebocytes and dose-dependently induce lipid production and (chiefly apoptosis-driven) cell death. Endocannabinoids also up-regulate the expression of key genes involved in lipid synthesis (e.g., PPAR transcription factors and some of their target genes). These actions are selectively mediated by CB2-coupled signaling involving the MAPK pathway, as revealed by specific agonists/antagonists and by RNA interference. Because cells with "silenced" CB2 exhibited significantly suppressed Basal lipid production, our results collectively suggest that human sebocytes utilize a paracrine-autocrine, endogenously active, CB2-mediated endocannabinoid signaling system for positively regulating lipid production and cell death. CB2 antagonists or agonists therefore deserve to be explored in the management of skin disorders characterized by sebaceous gland dysfunctions (e.g., acne vulgaris, seborrhea, dry skin).-Dobrosi, N., Tóth, B. I., Nagy, G., Dózsa, A., Géczy, T., Nagy, L., Zouboulis, C. C., Paus, R., Kovács, L., Bíró, T. Endocannabinoids enhance lipid synthesis and apoptosis of human sebocytes via cannabinoid receptor-2-mediated signaling.

Clin Cancer Res. 2008 Jul 1; 14(13): 4175-85
Allen C, Saigal K, Nottingham L, Arun P, Chen Z, Van Waes C

PURPOSE: Nuclear factor-kappaB (NF-kappaB)/REL transcription factors promote cancer cell survival and progression. The canonical (NF-kappaB1/RELA or cREL) and alternate (NF-kappaB2/RELB) pathways require the proteasome for cytoplasmic-nuclear translocation, prompting the investigation of bortezomib for cancer therapy. However, limited clinical activity of bortezomib has been observed in many epithelial malignancies, suggesting this could result from incomplete inhibition of NF-kappaB/RELs or other prosurvival signal pathways. EXPERIMENTAL DESIGN: To examine these possibilities, matched biopsies from 24 h posttreatment were obtained from accessible tumors of patients who received low-dose bortezomib (0.6 mg/m(2)) before reirradiation in a phase I trial for recurrent head and neck squamous cell carcinoma (HNSCC). Effects of bortezomib on apoptosis and proliferation by TUNEL and Ki67 staining were compared with nuclear staining for all five NF-kappaB subunits, phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated signal transducers and activators of transcription 3 (STAT3) in tumor biopsies, and by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTP) and DNA binding assay for the five NF-kappaB subunits in HNSCC cell lines. RESULTS: HNSCC showed increased nuclear staining for all five NF-kappaB subunits, phosphorylated ERK1/2, and phosphorylated STAT3. Bortezomib treatment significantly enhanced apoptosis with inhibition of nuclear RELA in three of four tumors, but other NF-kappaB subunits, ERK1/2, and STAT3 were variably or not affected, and tumor progression was observed within 3 months. In HNSCC cell lines, 10(-8) mol/L bortezomib inhibited cell density while inhibiting tumor necrosis factor-alpha-induced and partially inhibiting Basal activation of NF-kappaB1/RELA, but not NF-kappaB2/RELB. CONCLUSIONS: Although low-dose bortezomib inhibits activation of subunits of the canonical pathway, it does not block nuclear activation of the noncanonical NF-kappaB or other prosurvival signal pathways, which may contribute to the heterogeneous responses observed in HNSCC.

J Physiol. 2008 Jun 30;
Brooks SV, Vasilaki A, Larkin LM, McArdle A, Jackson MJ

Chronic exercise improves endurance and skeletal muscle oxidative capacity. Despite the potential importance of reactive oxygen species (ROS) generated during exercise as regulators of these adaptations, the effect of repeated bouts of aerobic exercise on ROS generation by skeletal muscles during contractions has not been examined. Our aim was to establish the impact of repeated treadmill running exercise on muscle ROS generation and activation of redox-sensitive transcription factors. Following 8 weeks of treadmill running, mice displayed an improvement in running speed that was associated with an enhanced ability of gastrocnemius (GTN) muscles to maintain force during a protocol of isometric contractions. In contrast to GTN muscles of cage-sedentary (SED) mice, muscles from exercised (EXER) mice did not release superoxide or nitric oxide during the isometric contractions. For male mice, Basal levels of NFkappaB and AP-1 DNA binding were increased by treadmill running, and the contraction-induced activation of NFkappaB and AP-1 observed in muscles of SED mice was absent in EXER muscles. Also in contrast to SED muscles, EXER muscles displayed no reductions in glutathione or protein thiol levels in response to contraction. Our observations of decreases for EXER compared with SED muscles in contraction-induced (i) ROS generation, (ii) activation of redox-sensitive signaling pathways, and (iii) ROS stress suggest that exercise conditioning enhances the ability of skeletal muscle to readily and rapidly detoxify ROS and/or reduces ROS generation, providing protection from ROS-induced damage and reducing signals that might act to mediate further unnecessary adaptations.

Gene Expr Patterns. 2008 Jul; 8(6): 376-81
Fujimi TJ, Aruga J

Upstream stimulatory factors (USF) 1 and 2 are members of the basic helix-loop-helix leucine zipper transcription factor family. They are considered to play critical roles in cell-cycle regulation and chromatin remodeling. Their gene expression patterns are considered ubiquitous but have not been fully investigated in terms of embryogenesis. We examined the expression of the genes encoding USF1 and USF2 in Xenopus laevis during embryonic development. Expression of both genes was first detected as maternal transcripts and was observed continuously throughout development. However, in situ hybridization analysis revealed that the two genes were expressed differentially. In the late blastula, both genes were expressed in the blastocoel roof and marginal zone. At the gastrula stage, USF2 was strongly expressed in the sensorial layer of the ectoderm and in the mesoderm, whereas USF1 expression was hardly detectable. From the neurula stage onward, expression of both genes was markedly enhanced in the neural tissues, neural crest, eye and otic vesicle. However, spatial expression of the genes within the neural tube differed in that the strongest USF1 signals were observed in the lateral region of the Basal plate and the strongest USF2 ones in the dorsal region of the neural tube. Expression of the two genes occurred in different mesoderm derivatives at the tailbud stage (USF1, somite; USF2, pronephros and lateral plate mesoderm of the tail region). USF1 was expressed in the notochord of the early neurula, but was lost at the stage.

Am J Physiol Gastrointest Liver Physiol. 2008 Jun 26;
Saito H, Terada T, Shimakura J, Katsura T, Inui KI

The intestinal H(+)/peptide cotransporter 1 (PEPT1) plays important roles as a nutrient and drug transporter. Previously, we reported that rat intestinal PEPT1 showed a diurnal rhythm, and that this rhythm is closely related to the feeding schedule. Furthermore, we also demonstrated that transcription factors, Sp1, Cdx2, and PPARalpha, contribute to the Basal, intestine-specific, and fasting-induced expression of PEPT1, respectively. In this study, to clarify the molecular mechanism governing the diurnal rhythm of PEPT1 expression, we compared expression profiles of these transcription factors under two kinds of feeding schedules. The intestinal Sp1 and Cdx2 did not show a circadian accumulation of mRNA or response to the daytime feeding regimen. Plasma free fatty acids, endogenous PPARalpha ligands, exhibited a robust circadian fluctuation in phase with that of PEPT1. However, subsequent experiments using PPARalpha null mice revealed the absence of any association between PEPT1's circadian rhythm and PPARalpha. We then focused on the clock genes (Clock, Bmal1, Per1-2, and Cry1) and clock-controlled gene, DBP. A robust and coordinated circadian expression of the clock genes was observed and daytime feeding entirely inverted the phase except for Clock. The expression of DBP was in phase with that of PEPT1 in both groups. Electrophoretic mobility shift assays and reporter assays revealed that DBP has the ability to bind the DBP-binding-site located in the distal promoter region of the rat PEPT1 gene and induce the transcriptional activity. These findings indicate that DBP plays pivotal roles in the circadian oscillation of PEPT1. Key words: SLC15A1, albumin D site-binding protein, clock gene, restricted feeding.

BMC Plant Biol. 2008; 8: 71
Guillaumie S, Goffner D, Barbier O, Martinant JP, Pichon M, Barrière Y

BACKGROUND: Silage maize is a major forage and energy resource for cattle feeding, and several studies have shown that lignin content and structure are the determining factors in forage maize feeding value. In maize, four natural brown-midrib mutants have modified lignin content, lignin structure and cell wall digestibility. The greatest lignin reduction and the highest cell wall digestibility were observed in the brown-midrib-3 (bm3) mutant, which is disrupted in the caffeic acid O-methyltransferase (COMT) gene. RESULTS: Expression of cell wall related genes was investigated in Basal and ear internodes of normal, COMT antisens (AS225), and bm3 maize plants of the INRA F2 line. A cell wall macro-array was developed with 651 gene specific tags of genes specifically involved in cell wall biogenesis. When comparing Basal (older lignifying) and ear (younger lignifying) internodes of the normal line, all genes known to be involved in constitutive monolignol biosynthesis had a higher expression in younger ear internodes. The expression of the COMT gene was heavily reduced, especially in the younger lignifying tissues of the ear internode. Despite the fact that AS225 transgene expression was driven only in sclerenchyma tissues, COMT expression was also heavily reduced in AS225 ear and Basal internodes. COMT disruption or down-regulation led to differential expressions of a few lignin pathway genes, which were all over-expressed, except for a phenylalanine ammonia-lyase gene. More unexpectedly, several transcription factor genes, cell signaling genes, transport and detoxification genes, genes involved in cell wall carbohydrate metabolism and genes encoding cell wall proteins, were differentially expressed, and mostly over-expressed, in COMT-deficient plants. CONCLUSION: Differential gene expressions in COMT-deficient plants highlighted a probable disturbance in cell wall assembly. In addition, the gene expressions suggested modified chronology of the different events leading to cell expansion and lignification with consequences far beyond the phenylpropanoid metabolism. The reduced availability of monolignols and S units in bm3 or AS225 plants led to plants also differing in cell wall carbohydrate, and probably protein, composition. Thus, the deficiency in a key-enzyme of the lignin pathway had correlative effects on the whole cell wall metabolism. Furthermore, the observed differential expression between bm3 and normal plants indicated the possible involvement in the maize lignin pathway of genes which up until now have not been considered to play this role.

Mol Cell Biol. 2008 Jun 23;
Stanojcic S, Lemaitre JM, Brodolin K, Danis E, Mechali M

Previous observations led to the conclusion that, in Xenopus eggs and during early development, DNA replication initiates at regular intervals but with no apparent sequence specificity. Conversely, here, we present evidence for site-specific DNA replication origins in Xenopus egg extracts. Using lambda DNA, we show that DNA replication origins are activated in clusters, in regions which contain closely spaced adenine or thymine asymmetric tracks used as preferential initiation sites. In agreement with this data, addition of AT-rich asymmetric sequences, as competitors, preferentially recruits ORC and inhibits sperm chromatin replication by increasing inter-origin spacing. We also show that the assembly of a transcription complex favors origin activity at the corresponding site, without necessarily eliminating the other origins. Thus, although Xenopus eggs have the ability to replicate any kind of DNA, AT-rich domains or transcription factors favor the selection of DNA replication origins without increasing the overall efficiency of DNA synthesis. These results suggest that asymmetric AT rich regions might be default elements which favor the selection of a DNA replication origin in a transcriptionnally silent complex, whereas other epigenetic elements, linked to the organization of domains for transcription, may have further evolved over this Basal layer of regulation.

J Cell Sci. 2008 Jul 1; 121(Pt 13): 2224-34
Solanas G, Porta-de-la-Riva M, Agustí C, Casagolda D, Sánchez-Aguilera F, Larriba MJ, Pons F, Peiró S, Escrivà M, Muñoz A, Duñach M, de Herreros AG, Baulida J

E-cadherin and its transcriptional repressor Snail1 (Snai1) are two factors that control epithelial phenotype. Expression of Snail1 promotes the conversion of epithelial cells to mesenchymal cells, and occurs concomitantly with the downregulation of E-cadherin and the upregulation of expression of mesenchymal genes such as those encoding fibronectin and LEF1. We studied the molecular mechanism controlling the expression of these genes in mesenchymal cells. Forced expression of E-cadherin strongly downregulated fibronectin and LEF1 RNA levels, indicating that E-cadherin-sensitive factors are involved in the transcription of these genes. E-cadherin overexpression decreased the transcriptional activity of the fibronectin promoter and reduced the interaction of beta-catenin and NF-kappaB with this promoter. Similar to beta-catenin, NF-kappaB was found, by co-immunoprecipitation and pull-down assays, to be associated with E-cadherin and other cell-adhesion components. Interaction of the NF-kappaB p65 subunit with E-cadherin or beta-catenin was reduced when adherens junctions were disrupted by K-ras overexpression or by E-cadherin depletion using siRNA. These conditions did not affect the association of p65 with the NF-kappaB inhibitor IkappaBalpha. The functional significance of these results was stressed by the stimulation of NF-kappaB transcriptional activity, both Basal and TNF-alpha-stimulated, induced by an E-cadherin siRNA. Therefore, these results demonstrate that E-cadherin not only controls the transcriptional activity of beta-catenin but also that of NF-kappaB. They indicate too that binding of this latter factor to the adherens junctional complex prevents the transcription of mesenchymal genes.

Prog Neurobiol. 2008 May 4;
van Neerven S, Kampmann E, Mey J

Retinoids are important signals in brain development. They regulate gene transcription by binding to retinoic acid receptors (RAR) and, as was discovered recently, a peroxisome proliferator-activated receptor (PPAR). Traditional ligands of PPAR are best known for their functions in lipid metabolism and inflammation. RAR and PPAR are ligand-activated transcription factors, which share members of the retinoid X receptor (RXR) family as heterodimeric partners. Both signal transduction pathways have recently been implicated in the progression of neurodegenerative and psychiatric diseases. Since inflammatory processes contribute to various neurodegenerative diseases, the anti-inflammatory activity of retinoids and PPARgamma agonists recommends them as potential therapeutic targets. In addition, genetic linkage studies, transgenic mouse models and experiments with vitamin A deprivation provide evidence that retinoic acid signaling is directly involved in physiology and pathology of motoneurons, of the Basal ganglia and of cognitive functions. The activation of PPAR/RXR and RAR/RXR transcription factors has therefore been proposed as a therapeutic strategy in disorders of the central nervous system.

Mol Endocrinol. 2008 Jun 11;
Ciccone NA, Lacza CT, Hou MY, Gregory SJ, Kam KY, Xu S, Kaiser UB

Although follicle-stimulating hormone (FSH) plays an essential role in controlling gametogenesis, the biology of FSHbeta transcription remains poorly understood, but is known to involve the complex interplay of multiple endocrine factors including gonadotropin-releasing hormone (GnRH). We have identified a GnRH-responsive element within the rat FSHbeta promoter containing an E-box and partial CRE site that are bound by the basic helix loop helix transcription factor family members, upstream stimulating factor (USF)-1/USF-2, and the basic leucine zipper member, cAMP response element binding protein (CREB), respectively. Expression studies with CREB, USF-1/USF-2, and activating protein-1 (AP-1) demonstrated that the USF transcription factors increased Basal transcription, an effect not observed if the cognate binding site was mutated. Conversely, expression of a dominant negative CREB mutant or CREB knockdown attenuated induction by GnRH, whereas dominant negative Fos or USF had no effect on the GnRH response. GnRH stimulation specifically induced an increase in phosphorylated CREB (P-CREB) occupation of the FSHbeta promoter, leading to the recruitment of CREB binding protein (CBP) to enhance gene transcription. In conclusion, a composite element bound by both USF and CREB serves to integrate signals for Basal and GnRH-stimulated transcription of the rat FSHbeta gene.

Pathobiology. 2008; 75(2): 95-103
Rakha EA, Reis-Filho JS, Ellis IO

Recent advances in high-throughput molecular technologies have made it possible to begin to tackle the molecular complexity of breast cancer and have contributed to the realisation that this biologic heterogeneity has implications for treatment. One of the major achievements of class discovery studies in breast cancer is the identification of a Basal-like subtype that is characterised by absence of expression of hormone receptors and HER2 and has molecular features in common with Basal/myoepithelial cells of the breast. Basal-like cancers have attracted attention as a poor prognostic class of tumours that lack the benefit of currently available targeted therapy. However, Basal-like cancer as a distinct class of tumours, which share a specific molecular profile, are characterised by high proliferative activity and express specific markers, is a good candidate for development of specific targeted therapy. It is likely that in the near future, the ongoing research studies and clinical trials will provide an evidence-based approach to the best treatment strategy that can be applied to these tumours. In this review, we discuss the main features of Basal-like tumours and recent evidence on the different available therapeutic approaches.

Pathobiology. 2008; 75(2): 85-94
Palacios J, Robles-Frías MJ, Castilla MA, López-García MA, Benítez J

Hereditary breast cancer arising in carriers of mutations in the BRCA1 and BRCA2 genes differs from sporadic breast cancer and from non-BRCA1/2 familial breast carcinomas. Most BRCA1 carcinomas have the Basal-like phenotype and are high-grade, highly proliferating, estrogen receptor-negative and HER2-negative breast carcinomas, characterized by the expression of Basal markers such as Basal keratins, P-cadherin and epidermal growth factor receptor. BRCA1 carcinomas frequently carry p53 mutations. The Basal-like phenotype is only occasionally found in BRCA2 carcinomas, which tend to be estrogen and progesterone receptor positive. BRCA1 and BRCA2 loss of heterozygosity is found in almost all BRCA1 and BRCA2 carcinomas, respectively. Both genotypes have a low frequency of HER2 expression/amplification. In addition, comparative genomic hybridization and array expression studies have revealed differences in chromosomal gains and losses as well as expression patterns between genotypes. Several studies have shown that hereditary carcinomas that are not attributable to BRCA1/2 mutations are heterogeneous and have phenotypic similarities to BRCA2 tumors. A small group of cases are secondary to mutations in other breast cancer susceptibility genes, such as p53, PTEN or CDH1. As a result of the low frequency of breast carcinomas attributable to mutations in these genes, it is very difficult to establish a specific phenotype for each genotype, other than the association of lobular carcinomas with CDH1 germline mutations. The pathological and molecular features of hereditary breast cancer can drive specific treatments and influence the process of mutation screening.

Dev Cell. 2008 Jun; 14(6): 867-76
Breuninger H, Rikirsch E, Hermann M, Ueda M, Laux T

Axis formation is one of the earliest patterning events in plant and animal embryogenesis. In Arabidopsis, the main axis of the embryo is evident at the asymmetric division of the zygote into a small, embryonic apical cell and a large extraembryonic Basal cell. Here we show that the homeobox genes WOX2 and WOX8, which are initially coexpressed in the zygote, act as complementary cell fate regulators in the apical and Basal lineage, respectively. Furthermore, WOX8 expression in the Basal cell lineage is required for WOX2 expression and normal development of the proembryo, suggesting an inductive mechanism. The identified WOX cascade is required for normal expression of a reporter gene of the auxin efflux carrier PIN1 and for the formation of auxin response maxima in the proembryo. Thus, our results link the spatial separation of WOX transcription factors to localized auxin response and the formation of the main body axis in the embryo.

Epigenetics. 2008 Mar-Apr; 3(2): 97-106
Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM

BACKGROUND: In animal models, variations in early maternal care are associated with differences in hypothalamic-pituitary-adrenal(HPA) stress response in the offspring, mediated via changes in the epigenetic regulation of glucocorticoid receptor (GR) gene (Nr3c1) expression. OBJECTIVE: To study this in humans, relationships between prenatal exposure to maternal mood and the methylation status of a CpG-rich region in the promoter and exon 1F of the human GR gene (NR3C1) in newborns and HPA stress reactivity at age three months were examined. RESULTS: Prenatal exposure to increased third trimester maternal depressed/anxious mood was associated with increased methylation of NR3C1 at a predicted NGFI-A binding site. Increased NR3C1 methylation at this site was also associated with increased salivary cortisol stress responses at 3 months, controlling for prenatal SRI exposure, postnatal age and pre and postnatal maternal mood. METHODS: The methylation status of a CpG-rich region of the NR3C1 gene, including exon 1F, in genomic DNA from cord blood mononuclear cells was quantified by bisulfite pyrosequencing in infants of depressed mothers treated with a serotonin reuptake inhibitor antidepressant (SRI) (n = 33), infants of depressed nontreated mothers (n = 13) and infants of non depressed/non treated mothers (n = 36). To study the functional implications of the newborn methylation status of NR3C1 in newborns, HPA function was assessed at three months using salivary cortisol obtained before and following a non noxious stressor and at a late afternoon Basal time. CONCLUSIONS: Methylation status of the human NR3C1 gene in newborns is sensitive to prenatal maternal mood and may offer a potential epigenetic process that links antenatal maternal mood and altered HPA stress reactivity during infancy.

Proteins. 2008 Jun 5;
Lowry DF, Hausrath AC, Daughdrill GW

Intrinsically unstructured proteins (IUP) are widespread in eukaryotes and participate in numerous cellular processes, but a structural explanation of the mechanisms they use to recognize and bind their diverse targets has proved elusive. transcriptional activator domains are one class of IUP that function by recruiting other factors into Basal transcription complexes. transcriptional activator domains are known to use electrostatic interactions for recognition, but it is unclear how this could be accomplished by a structurally heterogeneous ensemble. To investigate this question, we performed principal component analysis on the atomic contact maps of an experimentally restrained ensemble of the human p53 transcriptional activator domain. This analysis revealed that the ensemble is conspicuously nonrandom and permitted a straightforward identification of persistent structural features and their relative probabilities. It was observed that six predominant long-range contacts are combinatorially arranged in 13 clusters of structures. Potential surfaces of the aligned clusters showed that these contacts uniformly organize the negative charges of the highly acidic p53 transcriptional activator domain on one face of the clusters. This observation provides a structural basis for the recruitment of other factors into Basal transcription complexes and further supports the hypothesis that the structural ensembles of IUPs are not random and instead have evolved under selection to maintain specific structural features. Proteins 2008. (c) 2008 Wiley-Liss, Inc.