authoritative, comprehensive and systematic

Genetic dissection of ventral folding morphogenesis in mouse: embryonic visceral endoderm-supplied BMP2 positions head and heart

Artificial induction and disease-related conversion of the hepatic fate

Positive and negative regulation of developmental signaling by the endocytic pathway

Generation and interpretation of FGF morphogen gradients in vertebrates

Only scratching the cell surface: extracellular signals in cerebrum development

Microdeletion syndromes

Wnt signalling in mouse gastrulation and anterior development: new players in the pathway and signal output

How genetic modifiers influence the phenotype of spinal muscular atrophy and suggest future therapeutic approaches

New insights into the genetic basis of TAR (thrombocytopenia-absent radii) syndrome

Molecular consequences of animal breeding

Brick by brick: metabolism and tumor cell growth

Tumor cells display increased metabolic autonomy in comparison to non-transformed cells, taking up nutrients and metabolizing them in pathways that support growth and proliferation. Classical work in tumor cell metabolism focused on bioenergetics, particularly enhanced glycolysis and suppressed oxidative phosphorylation (the 'Warburg effect'). But the biosynthetic activities required to create daughter cells are equally important for tumor growth, and recent studies are now bringing these…

Volume 18, Issue 1, 01 February 2008, Pp 54-61
DeBerardinis, R.J. | Sayed, N. | Ditsworth, D. | Thompson, C.B.

NF-κB and cancer - identifying targets and mechanisms

A connection between inflammation and carcinogenesis has long been known, but the precise mechanisms are just beginning to be understood. NF-κB proteins, transcription factors which integrate stress signals and orchestrate immune responses, have also recently been linked to carcinogenesis. Hallmarks of cancer development include self-sufficiency in growth signals, insensitivity to growth-inhibitors, evasion of apoptosis, limitless replicative potential, tissue invasion and metastasis, and…

Volume 18, Issue 1, 01 February 2008, Pp 19-26
Naugler, W.E. | Karin, M.

HIF-1: upstream and downstream of cancer metabolism

Hypoxia-inducible factor 1 (HIF-1) plays a key role in the reprogramming of cancer metabolism by activating transcription of genes encoding glucose transporters and glycolytic enzymes, which take up glucose and convert it to lactate; pyruvate dehydrogenase kinase 1, which shunts pyruvate away from the mitochondria; and BNIP3, which triggers selective mitochondrial autophagy. The shift from oxidative to glycolytic metabolism allows maintenance of redox homeostasis and cell survival under…

Volume 20, Issue 1, 01 February 2010, Pp 51-56
Semenza, G.L.

Common vs. rare allele hypotheses for complex diseases

There has been growing debate over the nature of the genetic contribution to individual susceptibility to common complex diseases such as diabetes, osteoporosis, and cancer. The 'Common Disease, Common Variant (CDCV)' hypothesis argues that genetic variations with appreciable frequency in the population at large, but relatively low 'penetrance' (or the probability that a carrier of the relevant variants will express the disease), are the major contributors to genetic susceptibility to common…

Volume 19, Issue 3, 01 June 2009, Pp 212-219
Schork, N.J. | Murray, S.S. | Frazer, K.A. | Topol, E.J.

The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation

The Ras/mitogen activated protein kinase (MAPK) pathway is essential in the regulation of the cell cycle, differentiation, growth and cell senescence, all of which are critical to normal development. It is therefore not surprising that its dysregulation has profound effects on development. A class of developmental syndromes, the 'RASopathies', is caused by germline mutations in genes that encode protein components of the Ras/MAPK pathway. The vast majority of these mutations result in increased…

Volume 19, Issue 3, 01 June 2009, Pp 230-236
Tidyman, W.E. | Rauen, K.A.

Cancer-associated fibroblasts and tumor growth - bystanders turning into key players

Novel mechanisms, and molecular mediators, of the pro-tumorigenic effects of cancer-associated fibroblasts (CAFs) have been identified. These include CXCL12/SDF-1-mediated recruitment of bone marrow-derived endothelial precursor cell and pro-metastatic effects of CCL5. Co-culture experiments also suggest that CAFs can influence the drug-sensitivity of cancer cells. Comparisons of CAFs from different tumors have started to identify tumor-type specific differences in CAF gene expression and…

Volume 19, Issue 1, 01 February 2009, Pp 67-73
Östman, A. | Augsten, M.

Pathways connecting inflammation and cancer

Chronic and persistent inflammation contributes to cancer development and can predispose to carcinogenesis. Infection-driven inflammations are involved in the pathogenesis of approximately 15-20% of human tumors. However, even tumors that are not epidemiologically linked to pathogens are characterized by the presence of an inflammatory component in their microenvironment. Hallmarks of cancer-associated inflammation include the presence of infiltrating leukocytes, cytokines, chemokines, growth…

Volume 18, Issue 1, 01 February 2008, Pp 3-10
Allavena, P. | Garlanda, C. | Borrello, M.G. | Sica, A. | Mantovani, A.

The emerging field of dynamic lysine methylation of non-histone proteins

Post-translational modifications (PTMs) regulate protein structure and function. Lysine methylation abundantly decorates histone proteins and has recently been detected on non-histone proteins. In particular, the tumor suppressor and transcription factor p53 has provided a model for lysine methylation on a non-histone protein. As found for histones, lysine methylation is dynamic and can be reversed by demethylation. Lysine methylation regulates function via several distinct mechanisms. Methyl…

Volume 18, Issue 2, 01 April 2008, Pp 152-158
Huang, J. | Berger, S.L.

Targeting the PI3K signaling pathway in cancer

The phosphoinositide 3-kinase (PI3K) pathway is activated in a variety of different human cancers, and inhibitors of this pathway are under active development as anti-cancer therapeutics. In this review, we discuss the data supporting the use of PI3K pathway inhibitors in genetically and clinically defined cancers. This review focuses on their efficacy as single agents and in combination with other targeted therapies, specifically those targeting the MEK-ERK signaling pathway. © 2009 Elsevier…

Volume 20, Issue 1, 01 February 2010, Pp 87-90
Wong, K.-K. | Engelman, J.A. | Cantley, L.C.

The emerging functions of histone demethylases

Epigenetic information refers to heritable changes in gene function that are stable between cell divisions but which is not a result of changes in the DNA sequence. Part of the epigenetic mechanism has been ascribed to modifications of histones or DNA that affects the transcription of specific genes. In this context, post-translational modifications of histone tails, in particular methylation of lysines, are regarded as important for the storage of epigenetic information. Regulation of this…

Volume 18, Issue 2, 01 April 2008, Pp 159-168
Agger, K. | Christensen, J. | Cloos, P.A. | Helin, K.

Microenvironmental regulation of cancer development

Numerous studies have demonstrated that the tumor microenvironment not only responds to and supports carcinogenesis, but also actively contributes to tumor initiation, progression, and metastasis. During tumor progression all cells composing the tumor undergo phenotypic and epigenetic changes. Paracrine signaling between epithelial and stromal cells is important for the regulation of the proliferation, invasive, angiogenic, and metastatic behavior of cancer cells. Better understanding the…

Volume 18, Issue 1, 01 February 2008, Pp 27-34
Hu, M. | Polyak, K.

Recent advances in cancer stem cells

The theory of cancer stem cells states that a subset of cancer cells within a tumor has the ability to self-renew and differentiate. Only those cells within a tumor that have these two properties are called cancer stem cells. This concept was first demonstrated in the study of leukemia where only cells with specific surface antigen profiles were able to cause leukemia when engrafted into immunodeficient mice. In recent years solid tumors were studied utilizing similar techniques in mice. Human…

Volume 18, Issue 1, 01 February 2008, Pp 48-53
Cho, R.W. | Clarke, M.F.

Acquired resistance to tyrosine kinase inhibitors during cancer therapy

Selective tyrosine kinase inhibitors have emerged as important therapeutic agents in the treatment of a variety of human malignancies. Although several of these inhibitors have marked clinical activity, it is widely recognized that the overall value of these agents is substantially limited by the acquisition of drug resistance, which eventually arises in most, if not all treated patients. Mechanisms of drug resistance are beginning to be elucidated through the molecular analysis of clinical…

Volume 18, Issue 1, 01 February 2008, Pp 73-79
Engelman, J.A. | Settleman, J.

AngiomiRs-Key regulators of angiogenesis

The formation of new blood vessels through the process of angiogenesis is critical in vascular development and homeostasis. Aberrant angiogenesis leads to a variety of diseases, such as ischemia and cancer. Recent studies have revealed important roles for miRNAs in regulating endothelial cell (EC) function, especially angiogenesis. Mice with EC-specific deletion of Dicer, a key enzyme for generating miRNAs, display defective postnatal angiogenesis. Specific miRNAs (angiomiRs) have recently been…

Volume 19, Issue 3, 01 June 2009, Pp 205-211
Wang, S. | Olson, E.N.

Immune surveillance: a balance between protumor and antitumor immunity

Precancerous and malignant cells can induce an immune response which results in the destruction of transformed and/or malignant cells, a process known as immune surveillance. However, immune surveillance is not always successful, resulting in 'edited' tumors that have escaped immune surveillance. Immunoediting is not simply because of the absence of antitumor immunity, but is because of protumor immunity that blocks antitumor adaptive and innate responses, and promotes conditions that favor…

Volume 18, Issue 1, 01 February 2008, Pp 11-18
Ostrand-Rosenberg, S.

Biochemical mechanisms of gene regulation by polycomb group protein complexes

Polycomb group (PcG) proteins are transcriptional repressors that control expression of developmental regulator genes in animals and plants. Recent advances in our understanding of the PcG system include biochemical purifications that revealed a substantial variety in PcG complex composition. These different complexes contain distinct chromatin-modifying activities and engage in cross-talk with other chromatin modifications. Complementing these biochemical analyses, structural studies have…

Volume 19, Issue 2, 01 April 2009, Pp 150-158
Müller, J. | Verrijzer, P.

RNAi-dependent formation of heterochromatin and its diverse functions

Expression profiling of eukaryotic genomes has revealed widespread transcription outside the confines of protein-coding genes, leading to production of antisense and non-coding RNAs (ncRNAs). Studies in Schizosaccharomyces pombe and multicellular organisms suggest that transcription and ncRNAs provide a framework for the assembly of heterochromatin, which has been linked to various chromosomal processes. In addition to gene regulation, heterochromatin is crucial for centromere function, cell…

Volume 20, Issue 2, 01 April 2010, Pp 134-141
Grewal, S.I.S.

Nuclear neighborhoods and gene expression

The eukaryotic nucleus is a highly compartmentalized and dynamic environment. Chromosome territories are arranged nonrandomly within the nucleus and numerous studies have indicated that a gene's position in the nucleus can impact its transcriptional activity. Here, we focus on recent advances in our understanding of the influence of specific nuclear neighborhoods on gene expression or repression. Nuclear neighborhoods associated with transcriptional repression include the inner nuclear…

Volume 19, Issue 2, 01 April 2009, Pp 172-179
Zhao, R. | Bodnar, M.S. | Spector, D.L.

Duplication hotspots, rare genomic disorders, and common disease

The human genome is enriched in interspersed segmental duplications that sensitize approximately 10% of our genome to recurrent microdeletions and microduplications as a result of unequal crossing over. We review the recent discovery of recurrent rearrangements within these genomic hotspots and their association with both syndromic and nonsyndromic diseases. Studies of common complex genetic disease show that a subset of these recurrent events plays an important role in autism, schizophrenia,…

Volume 19, Issue 3, 01 June 2009, Pp 196-204
Mefford, H.C. | Eichler, E.E.

DNA repair deficiency as a therapeutic target in cancer

Inhibitors of DNA repair proteins have been used in cancer therapy, mostly to potentiate the effects of cytotoxic agents. However, tumor cells frequently exhibit deficiencies in the signalling or repair of DNA damage. These deficiencies probably contribute to pathogenesis of the disease, but they also present an opportunity to target the tumor. Recently, inhibitors of poly(ADP-ribose) polymerase (PARP) have been shown to be highly selective for tumor cells with defects in the repair of…

Volume 18, Issue 1, 01 February 2008, Pp 80-86
Martin, S.A. | Lord, C.J. | Ashworth, A.

Showering c-MET-dependent cancers with drugs

The receptor tyrosine kinase, c-MET and its ligand hepatocyte growth factor/scatter factor (HGF/SF) have become leading candidates for targeted cancer therapies. Inappropriate c-MET signaling through autocrine, paracrine, amplification, and mutational activation occurs in virtually all types of solid tumors (http://www.vai.org/met), contributing to one or a combination of proliferative, invasive, survival, or angiogenic cancer phenotypes. c-MET and HGF/SF participate in all stages of malignant…

Volume 18, Issue 1, 01 February 2008, Pp 87-96
Knudsen, B.S. | Vande Woude, G.

Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors

Biological systems are integrated networks constantly responding to internal and external stimulators. Understanding the intrinsic response to an imbalanced system provides the opportunity to develop therapeutic approaches to reinstate the natural balanced state. Increasing evidence suggests that members of the nuclear receptor superfamily integrate both inflammatory and metabolic signals to maintain homeostasis in immune cells such as macrophages and lymphocytes. PPAR and LXR are nuclear…

Volume 18, Issue 5, 01 October 2008, Pp 461-467
Hong, C. | Tontonoz, P.

The genetics of Parkinson's syndromes: a critical review

Genetic analysis has identified many loci designated as PARK loci (OMIM #168600). Many of these loci do not refer to idiopathic Parkinson's disease which is characterized by Lewy body pathology, but rather to clinical parkinsonisms. In this review, besides reviewing the genetic of the disorder, we argue that this designation is misleading and that if we seek to understand the pathogenesis, we should study the genetics of Lewy body diseases: these include not only idiopathic Parkinson's disease,…

Volume 19, Issue 3, 01 June 2009, Pp 254-265
Hardy, J. | Lewis, P. | Revesz, T. | Lees, A. | Paisan-Ruiz, C.

Prediction of individual genetic risk of complex disease

Most common diseases are caused by multiple genetic and environmental factors. In the last 2 years, genome-wide association studies (GWAS) have identified polymorphisms that are associated with risk to common disease, but the effect of any one risk allele is typically small. By combining information from many risk variants, will it be possible to predict accurately each individual person's genetic risk for a disease? In this review we consider the lessons from GWAS and the implications for…

Volume 18, Issue 3, 01 June 2008, Pp 257-263
Wray, N.R. | Goddard, M.E. | Visscher, P.M.

The nuclear envelope - a scaffold for silencing?

An increasing number of studies indicate that chromosomes are spatially organized in the interphase nucleus and that some genes tend to occupy characteristic zones of the nuclear volume. FISH studies in mammalian cells suggest a differential localization of active and inactive loci, with inactive heterochromatin being largely perinuclear. Recent genome-wide mapping techniques confirm that the nuclear lamina, which lies beneath the nuclear envelope, interacts preferentially with silent genes. To…

Volume 19, Issue 2, 01 April 2009, Pp 180-186
Towbin, B.D. | Meister, P. | Gasser, S.M.

mTOR in aging, metabolism, and cancer

Genetic architecture in autism spectrum disorder

Nucleosome remodelers in double-strand break repair

Multi-disciplinary methods to define RNA–protein interactions and regulatory networks

Chromatin organization and transcriptional regulation

Chromatin dynamics at the replication fork: there's more to life than histones

miRNA profiling of cancer

Chromosomal domains: epigenetic contexts and functional implications of genomic compartmentalization

The JNK signal transduction pathway

Cancer epigenomics: beyond genomics