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PubMed2003

Wellcome Trust Award Lecture. Chromatin-modifying enzymes in transcription and cancer.

In recent years, our view of how gene expression is controlled has changed dramatically. The discovery of enzymes that modify histones has revealed that transcription is an enzymically driven process. Such modifications can recruit specific proteins and mediate chromatin changes that affect transcription either positively or negatively. Important biological pathways leading to cell proliferation are under the control of these enzymes, and several of them are found deregulated in cancer. The hope is that chromatin-modifying enzymes will be a rich source of targets for drug discovery.

Acetylesterase↗

PubMed1999

Genetics of allergy and bronchial hyperresponsiveness.

Allergy and asthma are closely related complex diseases caused by a combination of both genetic and environmental influences. Two common genetic approaches, candidate gene studies and genome-wide screens, have been used to localize and evaluate potential genetic factors that confer susceptibility or modify the phenotype of these diseases. Four genome screens suggest multiple chromosomal locations likely to contain asthma and allergy genes and many potential candidate genes exist in these regions. These screens were performed in six different populations and identified many common susceptibility regions as well as novel regions for each population. Ideally, these genes may point towards key biological pathways that will eventually serve as targets for therapeutic agents.

Asthma↗

PubMed2001

Sleep disturbance in association with elevated pulse rate for prediction of mortality--consequences of mental strain?

OBJECTIVES: Sleep deprivation has experimentally been shown to adversely influence glucose metabolism, endocrine function and sympathovagal balance in young men without known serious disease. We investigated the impact of sleep problems and resting heart rate in a large sample of self-reported, healthy middle-aged men and women on long-term mortality. METHODS: In all 22,444 men and 10,902 women participated in a population-based health screening (71% mean attendance), including blood sampling and examination of blood pressure (BP) and pulse rate after 10 min supine rest, as well as a self-administered questionnaire on sleep problems. Mortality was assessed from national death registers. RESULTS: Sleep disturbances were related to increased cardiovascular risk factor levels at baseline in both sexes, and predicted total and cause-specific mortality after a mean of 12 years (women) and 17 years (men) of follow-up. In men, self-reported healthy at baseline, total mortality during follow-up was independently predicted by both sleep problems and increased resting heart rate, also after adjustment for smoking, body mass index (BMI), systolic BP, cholesterol, smoking and problematic alcohol drinking habits. A step-wise increased total mortality was shown in men reporting successively worse sleep problems and higher heart rate, highest hazard ratio 2.7 [95% confidence interval (CI) = 2.1-3.4] after adjustments, compared with men free from sleep problems and with normal heart rate. CONCLUSIONS: Sleep disturbance is a predictor of total and cause-specific mortality in both sexes, but only interacts with increased resting heart rate for this prediction in healthy men. Sleep problems correlated cross-sectional with disturbances in lipid and glucose metabolism, even after adjustment for degree of obesity and smoking. Sleep disturbance is a symptom for a biological pathway that is correlated to premature mortality. One possible explanation would be that it acts in concert with sympathetic nervous activation (SNA), both being consequences of chronic stress exposure.

Analysis of Variance↗

PubMed2001

Molecular epidemiology of preterm delivery: methodology and challenges.

Preterm delivery (PTD) appears to be a complex trait determined by both genetic and environmental factors. Few studies have examined genetic influence on PTD. The overall goal of our study is to examine major candidate genes of PTD and to test gene-environment interactions. Our study includes 500 preterm trios, including 500 preterm babies and their parents and 500 maternal age-matched term controls. We will perform the transmission/disequilibrium test (TDT) on candidate genes thought to be important in each of the four biological pathways of PTD: (1) decidual chorioamionotic inflammation: interleukin 1 (IL-1), IL-6, and tumour necrosis factor (TNF); (2) maternal and fetal stress: corticotropin-releasing hormone (CRH); (3) uteroplacental vascular lesions: methylenetereahydrofolate reductase (MTHFR); and (4) susceptibility to environmental toxins: GSTM1, GSTT1, CYP1A1, CYP2D6, CYP2E1, NAT2, NQO1, ALDH2, and EPHX. We will also perform standard case-control analyses on the 500 preterm cases and 500 term controls to examine gene-environment interactions. The major environmental, nutritional and social factors as well as clinical variables known or suspected to be associated with PTD will be used to test for gene-environment interactions. This study integrates epidemiological and clinical data as well as genetic markers along major pathogenic pathways of PTD. The findings from this study should improve our understanding of genetic influences on PTD and gene-environment interactions.

Adult↗

PubMed2001

Risk stratification and pathological mechanisms in preterm delivery.

The delivery of infants before 37 weeks gestation is a leading cause of perinatal mortality and morbidity in the United States. Traditional methods of predicting women at risk relying on obstetric history or premonitory symptoms (detected clinically or by tocodynamometry) are neither sensitive nor specific. Recent approaches to predicting preterm delivery have included sonographic measurement of cervical length and various biochemical assays. Although more sensitive than traditional methods, none of these alone exhibits sufficient accuracy to warrant widespread use. We contend that the failure of current approaches to predicting preterm delivery reflects an inadequate understanding of the underlying pathogenesis. Clinical and experimental evidence support the concept that most cases of preterm delivery reflect four pathogenic processes, which share a common final biological pathway leading to uterine contractions and cervical changes with or without premature rupture of membranes. These pathogeneses are: (1) activation of the maternal or fetal hypothalamic-pituitary-adrenal axis; (2) decidual-chorioamniotic or systemic inflammation; (3) decidual haemorrhage (i.e. abruption); and (4) pathological distention of the uterus. Our research seeks to combine the most useful biophysical and biochemical markers of such processes with optimal clinical and epidemiological predictors into a composite, easily applied risk tool. This integrated approach has the potential to identify at-risk asymptomatic patients with high sensitivity, specificity, and positive and negative predictive values, and also to ascertain underlying pathogenic processes that can lead to targeted therapy. To accomplish these goals, we employ logistic regression and artificial neural network models to assess and apply the appropriate weight to markers associated with each of the above pathogenic pathways, in addition to markers of the final common pathway leading to fetal membrane rupture, cervical extracellular matrix degradation, and myometrial activation. By combining these markers, we expect ultimately to produce a predictive model that is more robust than any existing method, and that identifies the relative contribution of each pathogenic process. Further analysis of this model using a neural network will enable us to identify asymptomatic patients destined to deliver preterm with high sensitivity, specificity, positive and negative predictive values, and to assess the relative contribution of each of the four distinct pathogeneses to this preterm delivery risk.

Adult↗

PubMed2000

Non-major histocompatibility complex dependent variations in lymphocyte activity between inbred mouse strains susceptible to various autoimmune diseases.

Transgenic techniques in inbred mouse strains are powerful tools to investigate the specific roles of genes in biological pathways and disease models. However, there is increasing concern over the influence of a variable genetic background in such experiments. To date there have been few investigations of the immunological differences between inbred mouse strains used in models of autoimmune diseases. Here we phenotyped lymph node cells and T-cell cytokine production in B10.Q (H2q), B10.RIII (H2r), C3H.Q (H2q), C3H. NB (H2p), NOD (H2g7), RIII/SJ (H2r) and DBA/1J (H2q) mice. We found several significant differences. The C3H strains and RIII/SJ lymph node cells had a high ratio of T cells/B cells (> 2 : 1) and a high ratio of CD4/CD8 positive cells (> 3 : 1), these strains are therefore denoted high T cell ratio (HiTR) strains. B10 strains and DBA/1, however, displayed an expansion of gammadeltaT cells after mitogen activation. T cells derived from C3H and DBA/1J strains produced more interleukin (IL)-4 than did T cells from B10 and NOD strains. DBA/1J and B10.Q showed a 10-fold increase in interferon (IFN)-gamma producing cells in the CD4+ T-cell population. Variation in the number of IL-2 and IFN-gamma producing T cells between the B10 major histocompatibility complex (MHC) congenic strains was the only difference possibly controlled by the MHC region. We conclude that non-MHC genes influence the numbers of T cells and B cells in lymph nodes, as well as IFN-gamma, IL-4 and IL-10 production by T cells.

Animals↗

PubMed2003

Functional neuroimaging of genetic variation in serotonergic neurotransmission.

Serotonin (5-hydroxytryptamine; 5-HT) is a potent modulator of the physiology and behavior involved in generating appropriate responses to environmental cues such as danger or threat. Furthermore, genetic variation in 5-HT subsystem genes can impact upon several dimensions of emotional behavior including neuroticism and psychopathology, but especially anxiety traits. Recently, functional neuroimaging has provided a dramatic illustration of how a promoter polymorphism in the human 5-HT transporter (5-HTT) gene, which has been weakly related to these behaviors, is strongly related to the engagement of neural systems, namely the amygdala, subserving emotional processes. In this commentary, we discuss how functional neuroimaging can be used to characterize the effects of polymorphisms in 5-HT subsystem genes on the response of neural circuits underlying the generation and regulation of mood and temperament as well as susceptibility to affective illness. We argue that in time, such knowledge will allow us to not only transcend phenomenological diagnosis and represent mechanisms of disease, but also identify at-risk individuals and biological pathways for the development of new treatments.

Amygdala↗

PubMed2006

The biological differences between ovarian serous carcinoma and diffuse peritoneal malignant mesothelioma.

Recent improvements in immunohistochemistry panels used for differentiating ovarian serous carcinoma/primary peritoneal carcinoma (OC/PPC) from diffuse malignant peritoneal mesothelioma (DMPM) have resulted in improved diagnostic rates for these tumors in both cytological and histological material. However, little is known about the biological characteristics that differentiate these two cancer types. We performed a comparative analysis of cancer-associated molecule expression data for a cohort consisting of up to 270 serous OC/PPC specimens (only peritoneal lesions) and 32 peritoneal MM. The molecules studied were nerve growth factor receptors (p75, p-TrkA), angiogenic factors (VEGF, IL-8, bFGF, heparanase), laminin receptors (the 67-kDa receptor and the alpha 6 integrin subunit), proteases (MMP-2), immune response mediators (HLA-G), and signaling molecules (the MAPK members ERK, JNK, and p38). The methods used were immunohistochemistry, Western blotting, and RT-PCR. DMPM specimens showed significantly higher expression of p75 (P < 0.001), p-TrkA (P < 0.001), and bFGF (P < 0.001), and significantly lower expression of the 67-kDa receptor (P < 0.001), alpha 6 integrin subunit (P = 0.025), VEGF (P < 0.001), IL-8 (P < 0.001), and HLA-G (P = 0.039) compared with OC/PPC. DMPM specimens showed higher activation ratio (phosphorylated/total enzyme ratio) of all three MAPK members (ERK, P = 0.017; JNK, P < 0.001; p38, P = 0.009) compared with OC/PPC. These data document significant differences in the expression of cancer- and metastasis-associated molecules in MM compared with ovarian carcinoma, and suggest that different biological pathways are involved in tumorigenesis and disease progression in these two tumors.

Biomarkers, Tumor↗

PubMed2004

Targeted therapies and radiation for the treatment of head and neck cancer: are we making progress?

Targeting specific biological pathways in tumor development has been heralded as a promising approach to the treatment of cancer. Familiar to most investigators are the studies done with epidermal growth factor receptor (EGFR) antagonists, but newer agents currently under development also target angiogenic or cell cycle pathways. EGFR activation stimulates many important signaling pathways associated with cancer development and progression, and importantly, resistance to radiation. Because EGFR overexpression portends for a worse outcome in patients with advanced head and neck cancer (HNC), selective targeting of this signaling pathway has gained attention. The agents selected for initial studies include monoclonal antibodies and tyrosine kinase inhibitors against EGFR. Encouraging laboratory findings in different xenografts resulted in rapid translation into the clinic. Results from initial clinical trials show rather surprisingly that only a minority of patients benefited from EGFR inhibition as monotherapy or in combination with chemotherapy. Current challenges for investigators are to determine (1). who will benefit from targeted agents and which agents are most appropriate to combine with radiation and/or chemotherapy, (2). how to sequence these agents with radiation and/or cytotoxic compounds, (3). reliable markers for patient selection and verification of effective blockade of signaling in vivo, and (4). mechanisms behind intrinsic or acquired resistance to targeted agents to facilitate rational development of multiple targeted therapy. Well-integrated laboratory-clinical research programs are needed to address these issues.

Combined Modality Therapy↗

PubMed2005

Menin molecular interactions: insights into normal functions and tumorigenesis.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease predisposed by heterozygous germline mutations in the MEN1 tumor suppressor gene. Biallelic loss of MEN1 resulting from small mutation and/or loss of heterozygosity occurs in a large tissue spectrum of MEN1 tumors or non-hereditary tumors. Mouse models of MEN1 underexpression or overexpression have also supported the tumor-suppressor effect of the MEN1 gene. Menin, the 610-amino-acid protein encoded by MEN1, is expressed ubiquitously and found predominantly in the nucleus. Sequence analyses do not reveal motifs of known function other than two nuclear localization sequences. Menin has been found to partner in vitro with a variety of proteins that comprise transcription factors, DNA processing factors, DNA repair proteins, and cytoskeletal proteins. The diverse functions of menin interactors suggest roles for menin in multiple biological pathways. Inactivation of menin switches its JunD partner from a downstream action of growth suppression to growth promotion. This is a plausible mechanism for menin tumorigenesis.

Animals↗

PubMed2005

Enhanced ROS-generation in lymphocytes from Alzheimer's patients.

INTRODUCTION: Reactive oxygen species (ROS) have been implicated in neurodegeneration and seem to be involved in the physiology and pathophysiology of several diseases, including normal aging and Alzheimer's disease (AD). Enhanced ROS production in aging or AD is not restricted to the brain, but can also been seen in several peripheral tissues. The objective of the present study was to evaluate whether the mechanisms involved in the generation of oxidative stress in normal senescence and Alzheimer's disease are identical or not. METHODS: We analysed intracellular basal levels of ROS in lymphocytes from AD patients and healthy young and aged not-demented subjects as well as ROS levels following stimulation with d-ribose and staurosporine in all three groups. ROS levels were measured by flow cytometry using the intracellular fluorescence dye dihydrorhodamine123 (DHR123). RESULTS: Our study shows that AD lymphocytes have increased basal levels of ROS, low susceptibility to ROS stimulation by 2-deoxy- D-ribose (dRib) and an increased response to staurosporine when compared with age-matched controls. DISCUSSION: The data suggest that the defect(s) responsible for enhanced ROS production in AD may involve different or additional biological pathways than those involved in enhanced ROS generation during aging.

Adult↗

PubMed2006

Multiple biomarkers for the prediction of first major cardiovascular events and death.

BACKGROUND: Few investigations have evaluated the incremental usefulness of multiple biomarkers from distinct biologic pathways for predicting the risk of cardiovascular events. METHODS: We measured 10 biomarkers in 3209 participants attending a routine examination cycle of the Framingham Heart Study: the levels of C-reactive protein, B-type natriuretic peptide, N-terminal pro-atrial natriuretic peptide, aldosterone, renin, fibrinogen, D-dimer, plasminogen-activator inhibitor type 1, and homocysteine; and the urinary albumin-to-creatinine ratio. RESULTS: During follow-up (median, 7.4 years), 207 participants died and 169 had a first major cardiovascular event. In Cox proportional-hazards models adjusting for conventional risk factors, the following biomarkers most strongly predicted the risk of death (each biomarker is followed by the adjusted hazard ratio per 1 SD increment in the log values): B-type natriuretic peptide level (1.40), C-reactive protein level (1.39), the urinary albumin-to-creatinine ratio (1.22), homocysteine level (1.20), and renin level (1.17). The biomarkers that most strongly predicted major cardiovascular events were B-type natriuretic peptide level (adjusted hazard ratio, 1.25 per 1 SD increment in the log values) and the urinary albumin-to-creatinine ratio (1.20). Persons with "multimarker" scores (based on regression coefficients of significant biomarkers) in the highest quintile as compared with those with scores in the lowest two quintiles had elevated risks of death (adjusted hazard ratio, 4.08; P<0.001) and major cardiovascular events (adjusted hazard ratio, 1.84; P=0.02). However, the addition of multimarker scores to conventional risk factors resulted in only small increases in the ability to classify risk, as measured by the C statistic. CONCLUSIONS: For assessing risk in individual persons, the use of the 10 contemporary biomarkers that we studied adds only moderately to standard risk factors.

Biomarkers↗

PubMed2004

The yeast cell-cycle network is robustly designed.

The interactions between proteins, DNA, and RNA in living cells constitute molecular networks that govern various cellular functions. To investigate the global dynamical properties and stabilities of such networks, we studied the cell-cycle regulatory network of the budding yeast. With the use of a simple dynamical model, it was demonstrated that the cell-cycle network is extremely stable and robust for its function. The biological stationary state, the G1 state, is a global attractor of the dynamics. The biological pathway, the cell-cycle sequence of protein states, is a globally attracting trajectory of the dynamics. These properties are largely preserved with respect to small perturbations to the network. These results suggest that cellular regulatory networks are robustly designed for their functions.

Cell Cycle↗

PubMed2005

From the Cover: Location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen response.

Nuclear receptors can activate diverse biological pathways within a target cell in response to their cognate ligands, but how this compartmentalization is achieved at the level of gene regulation is poorly understood. We used a genome-wide analysis of promoter occupancy by the estrogen receptor alpha (ERalpha) in MCF-7 cells to investigate the molecular mechanisms underlying the action of 17beta-estradiol (E2) in controlling the growth of breast cancer cells. We identified 153 promoters bound by ERalpha in the presence of E2. Motif-finding algorithms demonstrated that the estrogen response element (ERE) is the most common motif present in these promoters whereas conventional chromatin immunoprecipitation assays showed E2-modulated recruitment of coactivator AIB1 and RNA polymerase II at these loci. The promoters were linked to known ERalpha targets but also to many genes not directly associated with the estrogenic response, including the transcriptional factor FOXA1, whose expression correlates with the presence of ERalpha in breast tumors. We found that ablation of FOXA1 expression in MCF-7 cells suppressed ERalpha binding to the prototypic TFF1 promoter (which contains a FOXA1 binding site), hindered the induction of TFF1 expression by E2, and prevented hormone-induced reentry into the cell cycle. Taken together, these results define a paradigm for estrogen action in breast cancer cells and suggest that regulation of gene expression by nuclear receptors can be compartmentalized into unique transcriptional domains by means of licensing of their activity to cofactors such as FOXA1.

Base Sequence↗

PubMed2002

Paracrine in vivo inhibitory effects of hepatitis B virus X protein (HBx) on liver cell proliferation: an alternative mechanism of HBx-related pathogenesis.

The role of the hepatitis B virus X protein (HBx) in the pathogenesis of hepatitis B virus (HBV) infection remains unclear. HBx exhibits pleiotropic biological effects, whose in vivo relevance is a matter for debate. In the present report, we have used a combination of HBx-expressing transgenic mice and liver cell transplantation to investigate the in vivo impact of HBx expression on liver cell proliferation and viability in a regenerative context. We show that moderate HBx expression inhibits liver regeneration after partial hepatectomy in HBx-expressing transgenic mice. We also demonstrate that the transplantation of HBx-expressing liver cells, isolated from HBx transgenic mice, is sufficient to inhibit overall recipient liver regeneration after partial hepatectomy. Moreover, the injection of serum samples drawn from HBx-expressing transgenic mice mimicked the inhibitory effect of HBx on liver regeneration. Finally, the incubation of primary rat hepatocytes with the supernatant of HBx-expressing liver cells inhibits cellular DNA synthesis. Taken together, our results demonstrate a paracrine inhibitory effect of HBx on liver cell proliferation and lead us to propose HBV as one of the few viruses implicated in human cancer which act, at least in part, through paracrine biological pathways.

Animals↗

PubMed1985

Characterization of rate-controlling steps in vivo by use of an adjustable expression vector.

Citrate synthase (EC 4.1.3.7) was varied from 10% to 5000% the level found in wild-type Escherichia coli by means of recombinant DNA techniques. When acetate was the sole carbon source, cell growth and carbon flow through the Krebs cycle were greatly affected by the under-production of citrate synthase. In contrast, when glucose was the main nutrient, the same underproduction of citrate synthase had little effect on either growth or carbon flux. When the enzyme was overproduced 50-fold, cultures would grow on glucose but cell division could be abruptly stopped by adding acetate to the medium. These results indicate that the regulatory properties of citrate synthase are highly dependent on the carbon-source composition of the medium. Furthermore, recombinant DNA technology can be used to alter rate-controlling steps in biological pathways and elucidate the regulatory properties of metabolic systems.

Citrate (si)-Synthase↗

PubMed1996

Phosphatidylinositol 4,5-bisphosphate provides an alternative to guanine nucleotide exchange factors by stimulating the dissociation of GDP from Cdc42Hs.

Members of the Rho subfamily of Ras-related GTP-binding proteins play important roles in the organization of the actin cytoskeleton and in the regulation of cell growth. We have shown previously that the dbl oncogene product, which represents a prototype for a family of growth regulatory proteins, activates Rho subfamily GTP-binding proteins by catalyzing the dissociation of GDP from their nucleotide binding site. In the present study, we demonstrate that the acidic phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP2), provides an alternative mechanism for the activation of Cdc42Hs. Among a variety of lipids tested, only PIP2 was able to stimulate GDP release from Cdc42Hs in a dose-dependent manner, with a half-maximum effect at approximately 50 microM. Unlike the Dbl oncoprotein, which requires the presence of (free) guanine nucleotide in the medium to replace the GDP bound to Cdc42Hs, PIP2 stimulates GDP release from Cdc42Hs in the absence of free guanine nucleotide. PIP2, when incorporated into phosphatidylcholine carrier vesicles, binds tightly to the guanine nucleotide-depleted form of Cdc42Hs and weakly to the GDP-bound form of the GTP-binding protein but does not bind to GTP-bound Cdc42Hs, similar to what was observed for the Dbl oncoprotein. However, mutational analysis of Cdc42Hs indicates that the site that is essential for the functional interaction between PIP2 and Cdc42Hs is distinct from the Dbl-binding site and is located at the positively charged carboxyl-terminal end of the GTP-binding protein. The GDP-releasing activity of PIP2 is highly effective toward Cdc42Hs and Rho (and is similar to the reported effects of PIP2 on Arf (Terui, T., Kahn, R. A., and Randazzo, P. A., (1994) J. Biol. Chem. 269, 28130-28135)), is less effective with Rac, and is not observed with Ras, Rap1a, or Ran. The ability of PIP2 to activate Cdc42Hs (or Rho) and Arf provides a possible point of convergence for the biological pathways regulated by these different GTP-binding proteins and may be related to the synergism observed between Arf and Rho-subtype proteins in the stimulation of phospholipase D activity (Singer, W. D., Brown, H. A., Bokoch, G. M., and Sternweis, P. C. (1995) J. Biol. Chem. 270, 14944-14950).

Cell Cycle Proteins↗

PubMed1999

Rat B(2) sequences are induced in the hippocampal CA1 region after transient global cerebral ischemia.

Global brain ischemia causes cell death in the CA1 region of the hippocampus 3-5 days after reperfusion. The biological pathway leading to such delayed neuronal damage has not been established. By using differential display analysis, we examined expression levels of poly(A) RNAs isolated from hippocampal extracts prepared from rats exposed to global ischemia and found an up-regulated transcript, clone 17a. Northern blot analysis of clone 17a showed an approximately 35-fold increase in the ischemic brain at 24 h after four-vessel occlusion. Rapid amplification of cDNA ends of clone 17a revealed a family of genes (160-540 base pairs) that had the characteristics of rodent B(2) sequences. In situ hybridization demonstrated that the elevated expression of this gene was localized predominantly in the CA1 pyramidal neurons. The level of expression in the CA1 region decreased dramatically between 24 and 72 h after ischemia. The elevated expression of clone 17a was not observed in four-vessel occlusion rats treated with the compound LY231617, an antioxidant known to exert neuroprotection in rats subjected to global ischemia. Since delayed neuronal death has the characteristics of apoptosis, we speculate that clone 17a may be involved in apoptosis. We examined the expression level of clone 17a in in vitro models of apoptosis using cerebellar granule neurons that were subjected to potassium removal, glutamate toxicity, or 6-hydroxydopamine treatment and found that clone 17a transcripts were induced in cerebellar granule neurons by glutamate or 6-hydroxydopamine stimulation but not potassium withdrawal.

Amino Acid Sequence↗