Retinoblastoma tumor suppressor: where cancer meets the cell cycle

The retinoblastoma tumor suppressor gene, Rb, was the first tumor suppressor identified and plays a fundamental role in regulation of progression through the cell cycle. This review details facets of RB protein function in cell cycle control and focuses on specific questions that remain intensive areas of investigation.     

Population genetics of tumor suppressor genes

Cancer emerges when a single cell receives multiple mutations. For example, the inactivation of both alleles of a tumor suppressor gene (TSG) can imply a net reproductive advantage of the cell and might lead to clonal expansion. In this paper, we calculate the probability as a function of time that a population of cells has generated at least one cell with two inactivated alleles of a TSG. Different kinetic laws hold for small and large populations. The inactivation of the first allele can either be neutral or lead to a selective advantage or disadvantage. The inactivation of the first and of the second allele can occur at equal or different rates. Our calculations provide insights into basic aspects of population genetics determining cancer initiation and progression.     

The mouse: genetics meets behaviour

Genetic studies in the mouse are important in the elucidation of molecular pathways that underlie behaviour. The advantages of the mouse for behavioural studies include an extensive array of genetic technologies and an elaborate behavioural repertoire that can be used to create models of human disease. This review discusses the relative advantages of forward and reverse genetic approaches to studying the genetic basis of behaviour in the mouse, and the complexities that behavioural studies need to address, such as phenotypic variability, genetic background effects and pleiotropy.     

The tumor suppressor p53: Cancer and aging

Aging, like many other biological processes, is subject to regulation by genes that reside in pathways that have been conserved during evolution. The insulin/ IGF-1 pathway, mTOR pathway and p53 pathway are among those conserved pathways that impact upon longevity and aging-related diseases such as cancer. Most cancers arise in the last quarter of life span with the frequency increasing exponentially with time, and mutation accumulation in critical genes (e.g. p53) in individual cells over a lifetime is thought to be the reason. Recently, we found that the efficiency of the p53 response to stress decline significantly with age in mice, and the time of onset of this decreased p53 response correlates with the life span of mice. Given the crucial role of the p53 in tumor prevention, this decline in p53 activity at older ages in animals could contribute to the observed dramatic increases in cancer frequency, and provides a plausible explanation for the correlation between tumorigenesis and aging in addition to the accumulation of DNA mutations over lifetime. We discuss here the coordination and communication between the p53 pathway and the IGF-1-mTOR pathways, and their possible impact on cancer and longevity.     

Delineating oncogene/tumor suppressor interactions in human mammary epithelial cells

Comment on: Cipriano R, et al. Proc Natl Acad Sci USA 2011; 108:8668-73.     

Population genetics meets behavioral ecology

Populations are often composed of more than just randomly mating subpopulations - many organisms from social groups with distinct patterns of mating and dispersal. Such patterns have recieved much attention in behavioral ecology, yet theories of population genetics rarely take social structures into account. Consequently, population geneticists often report high levels of apparent in breeding and concomitantly low efective sizes, even for species that avoid mating between close kin. Recently, a view of gene dynamics has been introduced that takes dispersal and social structure into account. Accounting for social structure in population genetics leads to a different perspective on how genetic variation is partitoned and the rate at which genic diversity is lost in natural populations - a view that is more consistent with observed behaviors for the minimization of inbreeding.     

Plant transposable elements: where genetics meets genomics

Transposable elements are the single largest component of the genetic material of most eukaryotes. The recent availability of large quantities of genomic sequence has led to a shift from the genetic characterization of single elements to genome-wide analysis of enormous transposable-element populations. Nowhere is this shift more evident than in plants, in which transposable elements were first discovered and where they are still actively reshaping genomes.     

How flies get their size: genetics meets physiology

Body size affects important fitness variables such as mate selection, predation and tolerance to heat, cold and starvation. It is therefore subject to intense evolutionary selection. Recent genetic and physiological studies in insects are providing predictions as to which gene systems are likely to be targeted in selecting for changes in body size. These studies highlight genes and pathways that also control size in mammals: insects use insulin-like growth factor (IGF) and Target of rapamycin (TOR) kinase signalling to coordinate nutrition with cell growth, and steroid and neuropeptide hormones to terminate feeding after a genetically encoded target weight is achieved. However, we still understand little about how size is actually sensed, or how organ-intrinsic size controls interface with whole-body physiology.     

Nature meets nurture: molecular genetics of gastric cancer

The immensity of genes and molecules implicated in gastric carcinogenesis is overwhelming and the relevant importance of some of these molecules is too often unclear. This review serves to bring us up-to-date with the latest findings as well as to look at the larger picture in terms of how to tackle the problem of solving this multi-piece puzzle. In this review, the environmental nurturing of intestinal cancer is discussed, beginning with epidemiology (known causative factors for inducing molecular change), an update of H. pylori research, including the role of inflammation and stem cells in premalignant lesions. The role of E-cadherin in the nature (genotype) of diffuse gastric cancer is highlighted, and finally the ever growing discipline of SNP analysis (including IL1B) is discussed.     

Ecology meets molecular genetics in Arabidopsis

 Arabidopsis thaliana has been used as a model plant for molecular genetics studies. Recently, Arabidopsis has been utilized in an increasing number of ecological and evolutionary studies. These studies are beginning to explain three “black boxes” of ecology: the nature of the mutations responsible for phenotypic variation, female–male interactions in the pistil, and the genetic basis of speciation. Among the advances are the inclusive fitness of haploid gametophytes, the testing of the arms-race model, morphological diversity, and reproductive isolation. Important methods include quantitative trait locus (QTL) mapping and molecular population genetics. Most significantly, natural variations of various aspects are now available via the taxonomic revision of its closely related species, and by the worldwide collection of accessions. Some conspicuous works using maize, Drosophila, and other species will be also discussed. Received: June 1, 2002 / Accepted: October 15, 2002 Acknowledgments I would like to express my deepest gratitude to Prof. K. Okada for supporting this research. I thank the organizers of the symposium for fruitful discussion, T. Yahara and M. Kanaoka for critical reading, T. Araki and T. Kenta for valuable discussions, and members of the Okada laboratory for technical assistance and discussion. The work was supported by JSPS Research Fellowships for Young Scientists.     

Parent-offspring conflict and co-adaptation: behavioural ecology meets quantitative genetics

The evolution of the complex and dynamic behavioural interactions between caring parents and their dependent offspring is a major area of research in behavioural ecology and quantitative genetics. While behavioural ecologists examine the evolution of interactions between parents and offspring in the light of parent-offspring conflict and its resolution, quantitative geneticists explore the evolution of such interactions in the light of parent-offspring co-adaptation due to combined effects of parental and offspring behaviours on fitness. To date, there is little interaction or integration between these two fields. Here, we first review the merits and limitations of each of these two approaches and show that they provide important complementary insights into the evolution of strategies for offspring begging and parental resource provisioning. We then outline how central ideas from behavioural ecology and quantitative genetics can be combined within a framework based on the concept of behavioural reaction norms, which provides a common basis for behavioural ecologists and quantitative geneticists to study the evolution of parent-offspring interactions. Finally, we discuss how the behavioural reaction norm approach can be used to advance our understanding of parent-offspring conflict by combining information about the genetic basis of traits from quantitative genetics with key insights regarding the adaptive function and dynamic nature of parental and offspring behaviours from behavioural ecology.     

Assessing minimum viable population size: Demography meets population genetics

The discussion of a population's minimum viable size provides a focus for the study of ecological and genetic factors that influence the persistence of a threatened population. There are many causes of extinction and the fate of a specific population cannot generally be predicted. This uncertainty has been dealt with in two ways: through stochastic demographic models to determine how to minimize extinction probabilities; and through population genetic theory to determine how best to maintain genetic variation, in the belief that the ability to evolve helps buffer a population against the unknown. Recent work suggests that these two very different approaches lead to very similar conclusions, at least under panmictic conditions. However, defining the ideal spatial distribution for an endangered species remains an important challenge.     

Sclerotome development and morphogenesis: when experimental embryology meets genetics

The vertebra develops from the ventral part of the somite, the sclerotome. Sclerotome progenitors are subject to multiple signaling molecules secreted by the adjacent tissues that control their fate. The aim of this article is to discuss the mechanisms of sclerotome induction, chondrogenesis and morphogenesis. By integrating the results from classical studies and recent molecular advances, this will illustrate how the powerful combination of experimental embryology and genetic approaches has recently illuminated the multiple steps of vertebra formation.     

Proteoglycans and pattern formation: sugar biochemistry meets developmental genetics

While it has been long appreciated that sugar-modified proteins coat the cell surface, their functions are poorly understood. Here, I describe recent genetic studies that demonstrate that one class of sugar-modified proteins, cell-surface proteoglycans, play crucial roles in morphogenesis, growth regulation and tumor suppression. Mutations that affect individual proteoglycans or the enzymes required for glycosaminoglycan synthesis regulate Wingless and Decapentaplegic signaling in Drosophila, and body size in mice and humans. Compromising proteoglycan function is also associated with the development of Wilm's tumors and hereditary multiple exostoses. In this review, these biological findings are placed in the context of proteoglycan biochemistry and molecular function.