The hallmarks of cancer.

The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

/pdf/initial-sequencing-and-analysis-of-the-human-genome-5dapk1rsx1.pdf

Initial sequencing and analysis of the human genome.

The emergence of order in natural systems is a constant source of inspiration for both physical and biological sciences. While the spatial order characterizing for example the crystals has been the basis of many advances in contemporary physics, most complex systems in nature do not offer such high degree of order. Many of these systems form complex networks whose nodes are the elements of the system and edges represent the interactions between them. 
Traditionally complex networks have been described by the random graph theory founded in 1959 by Paul Erdohs and Alfred Renyi. One of the defining features of random graphs is that they are statistically homogeneous, and their degree distribution (characterizing the spread in the number of edges starting from a node) is a Poisson distribution. In contrast, recent empirical studies, including the work of our group, indicate that the topology of real networks is much richer than that of random graphs. In particular, the degree distribution of real networks is a power-law, indicating a heterogeneous topology in which the majority of the nodes have a small degree, but there is a significant fraction of highly connected nodes that play an important role in the connectivity of the network. 
The scale-free topology of real networks has very important consequences on their functioning. For example, we have discovered that scale-free networks are extremely resilient to the random disruption of their nodes. On the other hand, the selective removal of the nodes with highest degree induces a rapid breakdown of the network to isolated subparts that cannot communicate with each other. 
The non-trivial scaling of the degree distribution of real networks is also an indication of their assembly and evolution. Indeed, our modeling studies have shown us that there are general principles governing the evolution of networks. Most networks start from a small seed and grow by the addition of new nodes which attach to the nodes already in the system. This process obeys preferential attachment: the new nodes are more likely to connect to nodes with already high degree. We have proposed a simple model based on these two principles wich was able to reproduce the power-law degree distribution of real networks. Perhaps even more importantly, this model paved the way to a new paradigm of network modeling, trying to capture the evolution of networks, not just their static topology.

/pdf/statistical-mechanics-of-complex-networks-1zfjpvxipu.pdf

Statistical mechanics of complex networks

A genetic model for colorectal tumorigenesis

http://www.maths.qmul.ac.uk/%7Elatora/report_06.pdf

Complex networks: Structure and dynamics

The p53 gene is a tumor suppressor gene that plays a critical role in safeguarding the integrity of the genome. p53 is mutated or part of its regulatory circuit is functionally inactivated in almost all cancers, which highlights its importance in preventing tumorigenesis. The p53 protein is a

The p53 functional circuit.

It has been reported recently that the wild-type p53 gene product can positively regulate the expression of a test gene adjacent to the enhancer-promoter elements of the murine muscle-specific creatine kinase (MCK) gene. This discussion reports the identification of a wild-type p53 protein-specific DNA-binding element located within the p53-responsive region of the MCK enhancer-promoter element. This p53 protein/DNA-binding element has been defined by DNase I footprint analysis, which identified a 50-bp region. This 50-bp sequence was sufficient to confer wild-type p53 responsiveness on a heterologous minimal promoter. The mutant forms of p53 protein are much less capable of stimulating this DNA element. This study has identified the first example of a naturally occurring wild-type p53-specific DNA-binding element that is able to mediate positive regulation of a test gene. The results suggest a biological function in gene regulation for the wild-type p53 protein that is lost or altered in the mutant p53 proteins.

/pdf/wild-type-p53-mediates-positive-regulation-of-gene-ttvils9qbv.pdf

Wild-type p53 mediates positive regulation of gene expression through a specific DNA sequence element.

Over the past 10 years the signal transduction networks for p53, IGF-1-AKT, and TOR pathways have been assembled in worms, flies, and mammals, and their functions elucidated In the past 1-2 years a number of genes and their proteins have been identified that permit extensive communication and coordination between these pathways These three pathways are involved in sensing and integrating signals arising from nutrient and growth factor availability, signals from sensory and sexual organs, and intrinsic and extrinsic stress signals In turn these pathways regulate cell growth, proliferation, and death These networks are central to our understanding of a variety of physiological and pathological conditions, including cancer, diabetes, and longevity

/pdf/coordination-and-communication-between-the-p53-and-igf-1-akt-1torupcsph.pdf

Coordination and communication between the p53 and IGF-1–AKT–TOR signal transduction pathways

Twelve years ago, the Mdm2 oncogene was shown to bind to and inhibit the tumor suppressor protein, p53. During the past 12 years, both genetic and biochemical studies have demonstrated that Mdm2 is a key negative regulator of the tumor suppressor p53. Mdm2 and p53 form an oscillating auto-regulatory feedback loop, which is tightly controlled to allow the appropriate response to environmental stresses in order to suppress tumor formation. When Mdm2 activity is inappropriately heightened, as it is in many human tumors, p53 activity is attenuated and tumor susceptibility arises. The p53 gene is mutated in 50% of all human tumors, but in those tumors that retain wild type p53, inhibiting Mdm2 activity could activate p53 tumor suppression and therefore provide a therapeutic strategy for the treatment of cancer.

MDM2 is a Central Node in the p53 Pathway: 12 Years and Counting

WISP-1 (Wnt-1 induced secreted protein 1) is a member of the CCN family of growth factors. This study identifies WISP-1 as a beta-catenin-regulated gene that can contribute to tumorigenesis. The promoter of WISP-1 was cloned and shown to be activated by both Wnt-1 and beta-catenin expression. TCF/LEF sites played a minor role, whereas the CREB site played an important role in this transcriptional activation. WISP-1 demonstrated oncogenic activities; overexpression of WISP-1 in normal rat kidney fibroblast cells (NRK-49F) induced morphological transformation, accelerated cell growth, and enhanced saturation density. Although these cells did not acquire anchorage-independent growth in soft agar, they readily formed tumors in nude mice, suggesting that appropriate cellular attachment is important for signaling oncogenic events downstream of WISP-1.

/pdf/wisp-1-is-a-wnt-1-and-b-catenin-responsive-oncogene-5gtmyic12f.pdf

Arnold J. Levine

Papers

The p53 functional circuit.

Wild-type p53 mediates positive regulation of gene expression through a specific DNA sequence element.

Coordination and communication between the p53 and IGF-1–AKT–TOR signal transduction pathways

MDM2 is a Central Node in the p53 Pathway: 12 Years and Counting

WISP-1 is a Wnt-1- and β-catenin-responsive oncogene