authoritative, comprehensive and systematic

Small RNAs in development – insights from plants

Small temporal RNAs in animal development

Axial stem cells deriving both posterior neural and mesodermal tissues during gastrulation

Mutual exclusion of transcription factors and cell behaviour in the definition of vertebrate embryonic territories

Genome sequencing and cancer

Nuclear architecture by RNA

Active chromatin and noncoding RNAs: an intimate relationship

Small RNA in the nucleus: the RNA-chromatin ping-pong

Different means, same end—heterochromatin formation by RNAi and RNAi-independent RNA processing factors in fission yeast

Combinatorial complexity in chromatin structure and function: revisiting the histone code

The many ways of Wnt in cancer

More than 20 years ago, the oncogenicity of a Wnt ligand was revealed in a series of experiments originating with random proviral integration in mice. The significance of Wnt signaling in human cancer has since been buttressed by the identification of mutations in genes coding for the Wnt pathway components Axin, APC, and β-catenin. This review summarizes the reported genetic defects in the Wnt pathway, with an emphasis on their functional contribution to human tumor progression. © 2006…

Volume 17, Issue 1, 01 February 2007, Pp 45-51
Polakis, P.

We gather together: insulators and genome organization

When placed between an enhancer and promoter, certain DNA sequence elements inhibit enhancer-stimulated gene expression. The best characterized of these enhancer-blocking insulators, gypsy in Drosophila and the CTCF-binding element in vertebrates and flies, stabilize contacts between distant genomic regulatory sites leading to the formation of loop domains. Current results show that CTCF mediates long-range contacts in the mouse β-globin locus and at the Igf2/H19-imprinted locus. Recently…

Volume 17, Issue 5, 01 October 2007, Pp 400-407
Wallace, J.A. | Felsenfeld, G.

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.

Tetraploidy, aneuploidy and cancer

Aneuploidy is one of the most obvious differences between normal and cancer cells. However, there remains debate over how aneuploid cells arise and whether or not they are a cause or consequence of tumorigenesis. One proposed route to aneuploid cancer cells is through an unstable tetraploid intermediate. Supporting this idea, recent studies demonstrate that tetraploidy promotes chromosomal aberrations and tumorigenesis in vivo. These tetraploid cells can arise by a variety of mechanisms,…

Volume 17, Issue 2, 01 April 2007, Pp 157-162
Ganem, N.J. | Storchova, Z. | Pellman, D.

Hypoxia-inducible factors: central regulators of the tumor phenotype

Low oxygen levels are a defining characteristic of solid tumors, and responses to hypoxia contribute substantially to the malignant phenotype. Hypoxia-induced gene transcription promotes characteristic tumor behaviors, including angiogenesis, invasion, metastasis, de-differentiation and enhanced glycolytic metabolism. These effects are mediated, at least in part, by targets of the hypoxia-inducible factors (HIFs). The HIFs function as heterodimers comprising an oxygen-labile α-subunit and a…

Volume 17, Issue 1, 01 February 2007, Pp 71-77
Gordan, J.D. | Simon, M.C.

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.

Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation

The clinical implementation of array comparative genomic hybridization has revolutionized the diagnosis of patients with syndromic or nonsyndromic mental retardation. Multiple studies of hundreds of patients with idiopathic mental retardation, and normal karyotype and/or subtelomeric testing using genome-wide microarray platforms with ∼2000 to >30 000 (tiling-path) interrogating BAC/PAC probes have detected chromosome abnormalities in up to 17% of cases. Surprisingly, some of the pathogenic…

Volume 17, Issue 3, 01 June 2007, Pp 182-192
Stankiewicz, P. | Beaudet, A.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 multifaceted role of Notch in cancer

The diverse roles that Notch signals play during the development and maintenance of normal tissues are recapitulated in different forms of cancer. Depending on the tumor type, Notch can variously promote or limit tumor growth through either cell autonomous or cell non-autonomous effects on differentiation, cellular metabolism, cell cycle progression, angiogenesis, and possibly self-renewal and immune function. Of particular interest, recent findings indicate that a high fraction of T-cell acute…

Volume 17, Issue 1, 01 February 2007, Pp 52-59
Roy, M. | Pear, W.S. | Aster, J.C.

Cell cycle kinases in cancer

Cell division in mammalian cells is driven by protein kinases that regulate progression through the various phases of the cell cycle. Cyclin-dependent kinases (Cdks) regulate cell cycle commitment, DNA synthesis and the onset of mitosis. Kinases of the Aurora, Polo and Nek families participate in the centrosome cycle and modulate spindle function. Additional kinases such as Bub1, BubR1 and Mps1 regulate the spindle assembly checkpoint. It has been well established that misregulation of Cdks is…

Volume 17, Issue 1, 01 February 2007, Pp 60-65
Malumbres, M. | Barbacid, M.

New insight into BRAF mutations in cancer

There has been much recent progress in our understanding of the role played by the RAS-RAF-MEK-ERK cascade in human cancer. RAS is an oncogene and this pathway is known to promote proliferation and malignant transformation. More recently, however, RAF has become the focus of attention, particularly in melanoma, where approximately 70% of cases carry mutations in the BRAF gene. The majority of the mutations in BRAF in cancer are activating, but rare mutants that cannot activate MEK have provided…

Volume 17, Issue 1, 01 February 2007, Pp 31-39
Dhomen, N. | Marais, R.

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.

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.

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.

The role of Hox genes during vertebrate limb development

The potential role of Hox genes during vertebrate limb development was brought into focus by gene expression analyses in mice (P Dolle, JC Izpisua-Belmonte, H Falkenstein, A Renucci, D Duboule, Nature 1989, 342:767-772), at a time when limb growth and patterning were thought to depend upon two distinct and rather independent systems of coordinates; one for the anterior-to-posterior axis and the other for the proximal-to-distal axis (see D Duboule, P Dolle, EMBO J 1989, 8:1497-1505). Over the…

Volume 17, Issue 4, 01 August 2007, Pp 359-366
Zakany, J. | Duboule, D.

Consequences of genome duplication

Polyploidy has been widely appreciated as an important force in the evolution of plant genomes, but now it is recognized as a common phenomenon throughout eukaryotic evolution. Insight into this process has been gained by analyzing the plant, animal, fungal, and recently protozoan genomes that show evidence of whole genome duplication (a transient doubling of the entire gene repertoire of an organism). Moreover, comparative analyses are revealing the evolutionary processes that occur as…

Volume 17, Issue 6, 01 December 2007, Pp 505-512
Sémon, M. | Wolfe, K.H.

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 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.

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.

Differential adhesion in morphogenesis: a modern view

The spreading of one embryonic tissue over another, the sorting out of their cells when intermixed and the formation of intertissue boundaries respected by the motile border cells all have counterparts in the behavior of immiscible liquids. The 'differential adhesion hypothesis' (DAH) explains these liquid-like tissue behaviors as consequences of the generation of tissue surface and interfacial tensions arising from the adhesion energies between motile cells. The experimental verification of…

Volume 17, Issue 4, 01 August 2007, Pp 281-286
Steinberg, M.S.

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.

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.

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.

Stochastic gene expression: from single molecules to the proteome

Protein production involves a series of stochastic chemical steps. One consequence of this fact is that the copy number of any given protein varies substantially from cell to cell, even within isogenic populations. Recent experiments have measured this variation for thousands of different proteins, revealing a linear relationship between variance and mean level of expression for much of the proteome. This simple relationship is frequently thought to arise from the random production and…

Volume 17, Issue 2, 01 April 2007, Pp 107-112
Kaufmann, B.B. | van Oudenaarden, A.

The role of Shp2 (PTPN11) in cancer

Tyrosyl phosphorylation, which is controlled by protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs), regulates numerous cellular processes. Altered expression and/or mutations in PTKs are linked to many forms of cancer, yet until recently little was known about the roles of PTPs in normal cells or in cancer. Earlier work established that a member of the PTP superfamily, PTEN, is an important tumor suppressor gene. We now know that at least one other PTP, the SH2…

Volume 17, Issue 1, 01 February 2007, Pp 23-30
Mohi, M.G. | Neel, B.G.

Active chromatin and noncoding RNAs: an intimate relationship

Cellular senescence: putting the paradoxes in perspective

Chromatin higher-order structures and gene regulation

Screens, maps & networks: from genome sequences to personalized medicine

Opening Pandora's Box—the new biology of driver mutations and clonal evolution in cancer as revealed by next generation sequencing

Brick by brick: metabolism and tumor cell growth

Chromatin states in pluripotent, differentiated, and reprogrammed cells

Recent advances in pathway-targeted cancer drug therapies emerging from cancer genome analysis

Long non-coding RNAs and enhancers

Mechanisms for recurrent and complex human genomic rearrangements