Two different yeasts have a number of genes bearing striking structural and functional homologies to mammalian oncogenes. In yeast these genes are involved in the control of proliferation and early steps in the cell cycle. Many have putative protein kinase activity and some have been shown to control the activity of the enzyme adenylate cyclase which synthesizes cyclic AMP. Mutant forms of these yeast genes have oncogenic activity in mammalian cells.

Proto‐oncogene products may be multi‐functional proteins with various roles in cell differentiation as well as cell proliferation. The molecular biology of the gene products of three well characterized proto‐oncogenes (c‐fos, c‐myc and c‐src) are described, and the roles of three other proto‐oncogene products, involved in hormone and growth factor reception, are reviewed.

The relationships between oncogenes, cell‐cycle control genes, and growth‐related genes are described. An important generalization from the data is that all the oncogenes and cell‐cycle control genes so far characterized appear to be genes for growth factors or for receptors to growth factors, or to be involved in the general metabolism and structure of the cell. It is suggested that the transition in cell growth from quiescence to the proliferative state, in early G1, may be less specific than previously thought (...) and involve a general priming of the cells for more specific later stimuli. (shrink)

Oncogene activation leads to cellular transformation by deregulation of biological processes such as proliferation and metabolism. Paradoxically, this can also sensitize cells to nutrient deprivation, potentially representing an Achilles' heel in early stage tumors. The mechanisms underlying this phenotype include loss of energetic and redox homeostasis as a result of metabolic reprogramming, favoring synthesis of macromolecules. Moreover, an emerging mechanism involving the deregulation of mRNA translation elongation through inhibition of eukaryotic elongation factor 2 kinase (eEF2K) is presented. The potential (...) consequences of eEF2K deregulation leading to cell death under nutrient depletion are discussed. Finally, the relevance of eEF2K as a master regulator of the response to nutrient deprivation in vivo, and its potential exploitation for therapeutic targeting of cancers, are elaborated. Overall, a better understanding of the adaptive mechanisms allowing tumors to circumvent oncogene‐induced hypersensitivity to nutrient deprivation is a promising avenue for uncovering novel therapeutic targets in cancers. (shrink)

Between 1975 and 1985 a series of experiments demonstrated that cancer, whatever its causative agent, is due to the activation, by modification or overexpression, of a family of genes highly conserved during evolution, called the cellular oncogenes. These genes participate in the control of cell division in every living cell. Their products belong to the regulatory network relaying external signals from the membranes towards the nucleus and allowing cells to adapt their division rate to the demand of the organism. These (...) discoveries constitute what may be called the 'oncogene paradigm'. Although the existence of cellular oncogenes, assumed in early models of oncogenesis, was demonstrated as early as 1976, we will show in this article that this discovery was not sufficient for the development of the new paradigm. We will describe its slow and complex formation between 1980 and 1985 followed by its rapid acceptance by the scientific community. (shrink)

Small non‐coding RNAs (microRNAs or miRs) represent one of the most fertile areas of cancer research and recent advances in the field have prompted us to reconsider the traditional concept of cancer. Some miRs exert negative control over the expression of numerous oncoproteins in normal cells and consequently their deregulation is believed to be an important mechanism underlying cancer development and progression. Owing to their distinct patterns of expression associated with cancer type, remarkable stability and presence in blood and other (...) body fluids, miRs are considered to be highly promising cancer biomarkers. The identification of “miR signatures” associating cancer cell phenotypes with disease outcome and specific risk factor exposures will undoubtedly open new avenues for early diagnosis and therapy of cancer, as well as for the development of novel strategies for cancer prevention. (shrink)

Context can determine whether a given gene acts as an oncogene or a tumor suppressor. Deubiquitinating enzymes (DUBs) regulate the stability of many components of the pathways dictating cell fate so it would be expected that alterations in the levels or activity of these enzymes may have oncogenic or tumor suppressive consequences. In the current review we survey publications reporting that genes encoding DUBs are oncogenes or tumor suppressors. For many DUBs both claims have been made. For such “double (...) agents,” the effects of gain or loss of function will depend on the overall status of a complex of molecular signaling networks subject to extensive crosstalk. As the TGF‐β paradox makes clear context is critical in cell fate decisions, and the disconnect between experimental findings and patient survival outcomes can in part be attributed to disparities between culture conditions and the microenvironment in vivo. Convincing claims for oncogene or tumor suppressor roles require the documentation of gene alterations in patient samples; survival curves are alone inadequate. (shrink)

The study of adhesion plaques in normal and transformed cells provides a series of phenotypic markers by which the process of transformation can be followed. Several proteins which are concentrated in adhesion plaques have now been identified; a few of these can act as targets for tyrosine kinase. In an attempt to characterize the relationship between tyrosine phosphorylation and cell transformation, the reactions of three such proteins – vinculin, talin and integrin – with a range of tyrosine kinase oncogene (...) products have been studied in detail. (shrink)

We propose that the onset and progressive destructive action of cancer within an individual bears a profound and striking similarity to the onset and progressive human-engendered destruction of global ecosystems and the extinction of entire species. Cancer in the human body and our human role in planetary, especially biotic, degradation are uncannily similar systems. For starters, they are the only two known complex systems where a discrete component changes its normal ecological role and function—turning on and potentially killing its host, (...) and in so doing, itself. Both are “hostile takeovers.” Clearly, humans are integral to both systems. With cancer we are the host and victims of the rogue behavior of what starts out as a normal, healthy, and functionally important part of our bodies. With the biodiversity crisis, we are the part of the system that has changed, expanded, and proven so destructive to the system in which we live. We argue that given that these threats to our bodies and Earth are both essentially ecological diseases, understanding the critical role of ecological interdependencies for avoiding both cancer’s and humankind’s destruction of their respective homes should hopefully promote better stewardship of both by the only animal capable of recognizing the problems—us. (shrink)

Stem cells may have a special importance in the neoplastic behavior of certain lineages as well as in the normal development of these tissues. The role of oncogenes, and their normal cellular analogues, in stem cell behavior is therefore of special interest. This review describes recent results on the effects of virally‐mediated src‐gene transfer into hemopoietic stem cells in the physiological and developmental properties of these cells.

The following is adapted from the testimony, on 6 June 1984, of Dr T. G. Krontiris before the U.S. House Science and Technology Subcommittee on Investigations and Oversight, on the subject of oncogene research. In a previous report (BioEssays, 1, 3), the testimony of Dr C. J. Sherr, describing the molecular biology of oncogene action was given. Here, Krontiris describes the challenges in applying the new5ndings in diagnosis and therapy.

Cancer derives from a cell clone that has accumulated genetic and epigenetic changes that influence its phenotype and finally enable it to escape from the normal controls of proliferation. A recent paper shows that, in myc‐induced tumours, the inactivation of this oncogene produces the regression of the tumours and the differentiation of the tumour cells into mature osteocytes.1 In addition, a further reactivation of myc in these cells does not restore the malignant phenotype but induces apoptosis. This discovery could (...) lead to an innovative therapeutic strategy. BioEssays 25:104–107, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

In the past decades, an enormous amount of precious information has been collected about molecular and genetic characteristics of cancer. This knowledge is mainly based on a reductionistic approach, meanwhile cancer is widely recognized to be a ‘system biology disease’. The behavior of complex physiological processes cannot be understood simply by knowing how the parts work in isolation. There is not solely a matter how to integrate all available knowledge in such a way that we can still deal with complexity, (...) but we must be aware that a deeply transformation of the currently accepted oncologic paradigm is urgently needed. We have to think in terms of biological networks: understanding of complex functions may in fact be impossible without taking into consideration influences outside of the genome. Systems Biology involves connecting experimental unsupervised multivariate data to mathematical and computational approach than can simulate biologic systems for hypothesis testing or that can account for what it is not known from high-throughput data sets. Metabolomics could establish the requested link between genotype and phenotype, providing informations that ensure an integrated understanding of pathogenic mechanisms and metabolic phenotypes and provide a screening tool for new targeted drug. (shrink)

Genes that exert their function when they are introduced into a foreign genetic background pose many questions to our current understanding of the forces and mechanisms that promote either the maintenance or divergence of gene functions over evolutionary time. The melanoma inducing Xmrk oncogene of the Southern platyfish (Xiphophorus maculatus) is a stable constituent of the genome of this species. It displays its tumorigenic function, however, almost exclusively only after inter‐populational or, even more severely, interspecific hybridization events. The Xiphophorus (...) hybrid melanoma system has gained attention in biomedical research as a genetic model for studying tumor formation. From an evolutionary perspective, a prominent question is: how could this gene persist over millions of years? An attractive hypothesis is that Xmrk, acting as a detrimental gene in a hybrid genome, could be a speciation gene that shields the gene pool of its species from mixing with other closely related sympatric species. In this article, I briefly review our current knowledge of the molecular genetics and biochemical functions of the Xmrk gene and discuss aspects of its evolutionary history and presence with respect to this idea. While Xmrk as a potentially injurious oncogene has clearly survived for millions of years, its role as a speciation gene has to be questioned. BioEssays 30:822–832, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The Wnt family of developmental regulators were named after the Drosophila segmentation gene wingless and the murine proto‐oncogene int‐1. Homology between these two genes connected oncogenesis to cell‐cell signals in development. I review how wingless was initially characterized, and cloned, as part of the quest to identify developmental cell‐to‐cell signals, based on predictions of the Positional Information Model, and on the properties of homeotic and segmentation gene mutants. The requirements and cell‐nonautonomy of wingless in patterning multiple embryonic and adult (...) structures solidified its status as a candidate signaling molecule. The physical location of wingless mutations and transcription unit defined the gene and its developmental transcription pattern. When the Drosophila homolog of int‐1 was then isolated, and predicted to encode a secreted proto‐oncogene homolog, it's identity to the wingless gene confirmed that a developmental cell‐cell signal had been identified and connected cancer to development. (shrink)

Transmembrane receptor tyrosine kinases that bind to peptide factors transmit essential growth and differentiation signals. A growing list of orphan receptors, of which some are oncogenic, holds the promise that many unknown ligands may be discovered by tracking the corresponding surface molecules. The neu gene (also called erbB‐2 and HER‐2) encodes such a receptor tyrosine kinase whose oncogenic potential is released in the developing rodent nervous system through a point mutation. Amplification and overexpression of neu are thought to contribute to (...) malignancy of certain human adenocarcinomas. The search for soluble factors that interact with the Neu receptor led to the discovery of a 44 kDa glyco‐protein that induces phenotypic differentiation of cultured mammary tumor cells to growth‐arrested and milk‐producing cells. The Neu differentiation factor (NDF or heregulin), however, also acts as a mitogen for epithelial, Schwann and glial cells. Multiple forms of the factor are produced by alternative splicing and their expression is confined predominantly to the central and to the peripheral nervous systems. One identified neuronal function of this family of polypeptides is to control the formation of neuromuscular junctions, but their physiological role in secretory epithelia is still unknown. Other open questions relate to the transmembrane topology of various precursors, the identity of a putative co‐receptor, the possible existence of additional ligands of Neu and the functional significance of the interaction between Neu and at least three highly related receptor tyrosine kinases. (shrink)

The c‐myc proto‐oncogene is believed to be involved in the regulation of cell growth and differentiation. Deregulation of this gene, resulting in an inappropriate increase of gene product, can contribute to cancer formation. One of the ways in which the expression of the c‐myc gene can be deregulated is by the stabilization of the labile c‐myc mRNA. The rapid degradation of the c‐myc transcript appears to be mediated by at least two distinct regions in the mRNA. One lies in (...) the 3' untranslated region, and presumably consists of (A+U)‐rich sequences. The other lies in the C‐terminal part of the coding region and colocalizes with sequences encoding protein‐dimerization motifs. The exact mechanism by which the destabilizing elements function is not yet clear. Shortening of the poly(A) tail of the c‐myc message appears to precede degradation of the transcript. When translation is blocked, this shortening is slowed down and the mRNA is stabilized. This suggests that deadenylation is required before degradation of the mRNA body can take place. (shrink)

An understanding of underlying mechanisms involved in the activation of HIF‐1 in response to both hypoxic stress and oncogenic signals has important implications for how these processes may become deregulated in human cancer. Changes in microenvironmental stimuli such as hypoxia and growth factors in combination with genetic lesions, such as loss or inactivation of p53, PTEN or pVHL or oncogenic activation, can all lead to increased HIF‐1 activity. This provides cancer cells with a distinct advantage for survival and proliferation, resulting (...) in their ability to form vascular tumours, which are aggressive and metastatic. Accordingly, upregulation of HIF‐1α, a key component of HIF‐1, correlates with a poor treatment outcome using conventional therapies. A variety of mechanisms exist that regulate expression of HIF‐1α. In recent years, it has become clear that an extensive network of signalling cascades converge on HIF‐1α to regulate the transcriptional response. A better understanding of this regulation may provide a basis for the development of new cancer therapies. BioEssays 26:262–269, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

An understanding of underlying mechanisms involved in the activation of HIF‐1 in response to both hypoxic stress and oncogenic signals has important implications for how these processes may become deregulated in human cancer. Changes in microenvironmental stimuli such as hypoxia and growth factors in combination with genetic lesions, such as loss or inactivation of p53, PTEN or pVHL or oncogenic activation, can all lead to increased HIF‐1 activity. This provides cancer cells with a distinct advantage for survival and proliferation, resulting (...) in their ability to form vascular tumours, which are aggressive and metastatic. Accordingly, upregulation of HIF‐1α, a key component of HIF‐1, correlates with a poor treatment outcome using conventional therapies. A variety of mechanisms exist that regulate expression of HIF‐1α. In recent years, it has become clear that an extensive network of signalling cascades converge on HIF‐1α to regulate the transcriptional response. A better understanding of this regulation may provide a basis for the development of new cancer therapies. BioEssays 26:262–269, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Development of gene transfer systems provides a key tool for understanding gene function. Exciting and often unexpected consequences from embryo manipulations are yielding insights into molecular mechanisms underlying development under normal and pathogenic states, and are providing animal models for diseases. Contributing to this progress is the elegant work on c‐fos(1), where Wagner and coworkers identify this proto‐oncogene as a primary factor which directs cell differentiation along the osteoclast/macrophage lineages, and thus regulates bone remodeling. Their studies support a link (...) between skeletogenesis, marrow formation and hematopoiesis, and may help to delineate mechanisms underlying the oncogenic transformation of skeletal and hematopoietic cells. (shrink)

Contemporary oncological research is predominantly characterised by genetic explanations, a situation which may be briefly denoted as the oncogene paradigm. This essay discusses why the new paradigm was perceived so attractive that it could take over the whole field of oncology within a time-span of less than two decades. It is argued that the revolutionary character of the oncogene paradigm stems from the fact that it transcends a dichotomy which has kept experimental cancer research divided for more than (...) three quarters of a century. This concerns the dichotomy between so-called exogenous and endogenous explanations of cancer causation. This essay mainly focuses on the role of the exogenous/endogenous dichotomy in the reception of research on oncogenic viruses, especially discussing the work of Nobel laureate Peyton Rous on cancer viruses at the Rockefeller Institute. Rous was severely criticised by James Ewing, director of the Memorial Hospital for Cancer and Allied Diseases in New York, who held the idea that the origin of cancer was based in the cell. The twentieth century controversy over oncogenic viruses is placed in the context of the intense discussion over causality in medicine during the first decades of the twentieth century in Germany. It is argued that the oncogene paradigm may be seen as revolutionary because it succeeded in uniting the exogenous and endogenous explanations of cancer in a single paradigm. (shrink)

The proteins encoded by early region 1 A (E1A) of human adenoviruses (Ad) modulate the expression of both adenovirus genes and various host cell genes. With these transcription‐regulating properties the E1A proteins redirect the cell's metabolism, which enables them to induce oncogenic transformation in rodent cells. The E1A proteins modulate transcription by interacting both with gene‐specific and general cellular transcription factors. Various members of the AP‐1 and ATF/CREB families of transcription factors are targets for E1A‐dependent regulation, including cJun, the protein (...) product of the c‐jun proto‐oncogene. The E1A proteins modulate cJun‐dependent transcription both positively and negatively, and affect the activity as well as the expression levels of cJun. By increasing the phosphorylation status of cJun, E1A can stimulate transcription regulated by cJun/ATF2 heterodimers. In contrast, E1A inhibits the expression of various metalloproteases by interfering with the DNA‐binding capacity of cJun/cJun and cJun/cFos dimers, which might involve the association of E1A with the putative transcriptional coactivator p300. Since the ability of E1A to alter cJun‐dependent transcription correlates with its transforming capacity, interference with cJundependent transcription may be an essential step in E1A‐induced transformation. (shrink)

The c‐myc proto‐oncogene is normally subject to complex regulation at the transcriptional and post‐transcriptional levels in proliferating and differentiating cells. It is activated in response to growth stimuli and generally, though not always, repressed in response to differentiation signals. Abnormal, deregulated c‐myc expression is a common feature of numerous malignancies and occurs by a variety of molecular mechanisms which probably reflect the existence of multiple factors responsible for its normal control. Here, I provide a detailed summary of recent progress (...) and current views on c‐myc gene regulation. (shrink)

Mutations in growth factor receptor signaling pathways are common in cancer cells, including the highly lethal brain tumor glioblastoma (GBM) where they drive tumor growth through mechanisms including altering the uptake and utilization of nutrients. However, the impact of changes in micro‐environmental nutrient levels on oncogenic signaling, tumor growth, and drug resistance is not well understood. We recently tested the hypothesis that external nutrients promote GBM growth and treatment resistance by maintaining the activity of mechanistic target of rapamycin complex 2 (...) (mTORC2), a critical intermediate of growth factor receptor signaling, suggesting that altered cellular metabolism is not only a consequence of oncogenic signaling, but also potentially an important determinant of its activity. Here, we describe the studies that corroborate the hypothesis and propose others that derive from them. Notably, this line of reasoning raises the possibility that systemic metabolism may contribute to responsiveness to targeted cancer therapies. (shrink)

The integrated stress response (ISR) is a key determinant of tumorigenesis in response to oncogenic forms of stress like genotoxic, proteotoxic and metabolic stress. ISR relies on the phosphorylation of the translation initiation factor eIF2 to promote the translational and transcriptional reprogramming of gene expression in stressed cells. While ISR promotes tumor survival under stress, its hyperactivation above a level of tolerance can also cause tumor death. The tumorigenic function of ISR has been recently demonstrated for lung adenocarcinomas (LUAD) with (...) KRAS mutations. ISR mediates the translational repression of the dual‐specificity phosphatase DUSP6 to stimulate ERK activity and LUAD growth. The significance of this finding is highlighted by the strong anti‐tumor responses of ISR inhibitors in pre‐clinical LUAD models. Elucidation of the mechanisms of ISR action in LUAD progression via cell‐autonomous and immune regulatory mechanisms will provide a better understanding of its tumorigenic role to fully exploit its therapeutic potential in the treatment of a deadly form of cancer. (shrink)

Once regarded as cellular ‘debris’ extracellular vesicles (EVs) emerge as one of the most intriguing entities in cancer pathogenesis. Intercellular trafficking of EVs challenges the notion of cancer cell autonomy, and highlights the multicellular nature of such fundamental processes as stem cell niche formation, tumour stroma generation, angiogenesis, inflammation or immunity. Recent studies reveal that intercellular exchange mediated by EVs runs deeper than expected, and includes molecules causative for cancer progression, such as oncogenes (epidermal growth factor receptor, Ras), and tumour (...) suppressors (PTEN). The uptake of oncogenic EVs (oncosomes) by various cells may profoundly change their biology, signalling patterns and gene expression, and in some cases cause their overt tumorigenic conversion. Moreover, EVs circulating in blood and present in body fluids provide an unprecedented access to the molecular circuitry driving cancer cells, and new technologies are being developed to exploit this property as a source of unique cancer biomarkers. (shrink)

Oncogenes are altered forms of normal cellular genes known as proto‐oncogenes. Several oncogenes encode enzymes that phosphorylate substrate proteins at tyrosine. In most of these cases the oncogene differs from its proto‐oncogene by multiple mutations that alter the structure of the encoded protein product. Here we discuss how structural changes might effect the regulation and substrate specificity of the protein kinase product of a protooncogene so that it gains the potential to transform cells.

Oncogenic transformation is often associated with aberrant glycosylation in experimental and human tumors. The carbohydrate epitopes, resulting either from incomplete synthesis or neosynthesis, accumulate in high density, possibly in a novel conformation, at the tumor cell surface. A variety of monoclonal antibodies have been developed that recognize tumor‐associated carbohydrate antigens and their aberrant organization at the cell surface. These carbohydrate epitopes and the antibodies specific to these structures are being exploited to develop novel diagnostic tools and therapeutic strategies for cancer.

Oncogenic hyperplasia is the first and inevitable stage of formation of a (solid) tumor. This stage is also the core of many other proliferative diseases. The present work proposes the first minimal model that combines homeorhesis with oncogenic hyperplasia where the latter is regarded as a genotoxically activated homeorhetic dysfunction. This dysfunction is specified as the transitions of the fluid of cells from a fluid, homeorhetic state to a solid, hyperplastic-tumor state, and back. The key part of the model is (...) a nonlinear reaction-diffusion equation (RDE) where the biochemical-reaction rate is generalized to the one in the well-known Schlögl physical theory of the non-equilibrium phase transitions. A rigorous analysis of the stability and qualitative aspects of the model, where possible, are presented in detail. This is related to the spatially homogeneous case, i.e. when the above RDE is reduced to a nonlinear ordinary differential equation. The mentioned genotoxic activation is treated as a prevention of the quiescent G0-stage of the cell cycle implemented with the threshold mechanism that employs the critical concentration of the cellular fluid and the nonquiescent-cell-duplication time. The continuous tumor morphogeny is described by a time-space-dependent cellular-fluid concentration. There are no sharp boundaries (i.e. no concentration jumps exist) between the domains of the homeorhesis- and tumor-cell populations. No presumption on the shape of a tumor is used. To estimate a tumor in specific quantities, the model provides the time-dependent tumor locus, volume, and boundary that also points out the tumor shape and size. The above features are indispensable in the quantitative development of antiproliferative drugs or therapies and strategies to prevent oncogenic hyperplasia in cancer and other proliferative diseases. The work proposes an analytical-numerical method for solving the aforementioned RDE. A few topics for future research are suggested. (shrink)

The vav proto‐oncogene encodes a 95 kDa protein which is expressed exclusively in hematopoietic cells. Analysis of the deduced amino acid sequence has revealed the presence of a src‐homology 2 (SH2) domain, 2 SH3 domains, a cysteine‐rich region with similarity to protein kinase C, and a region highly similar to proteins with guanine nucleotide exchange activity on ras‐like GTPases. Recent work has shown that vav is tyrosine phosphorylated in response to stimulation of surface membrane receptors in a variety of (...) hematopoietic cell lines. Vav may play a role in hematopoietic cell signaling by coupling tyrosine kinase pathways to ras‐like GTPases through the regulation of guanine nucleotide exchange. (shrink)

The somatic mutation theory has been the prevailing paradigm in cancer research for the last 50 years. Its premises are: (1) cancer is derived from a single somatic cell that has accumulated multiple DNA mutations, (2) the default state of cell proliferation in metazoa is quiescence, and (3) cancer is a disease of cell proliferation caused by mutations in genes that control proliferation and the cell cycle. From this compelling simplicity, an increasingly complicated picture has emerged as more than 100 (...) oncogenes and 30 tumor suppressor genes have been identified. To accommodate this complexity, additional ad hoc explanations have been postulated. After a critical review of the data gathered from this perspective, an alternative research program has been proposed. It is based on the tissue organization field theory, the premises of which are that carcinogenesis represents a problem of tissue organization, comparable to organogenesis, and that proliferation is the default state of all cells. The merits of these competing theories are evaluated herein. BioEssays 26:1097–1107, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Illuminating insights into lymphoid oncogenesis came with the finding that the chromosome translocations characteristic of many tumors of immunoglobulin‐producing cells represent conjunction of an immunoglobulin gene locus with the myc oncogene. The potency of this combination has been underlined by recent studies in which DNA regions mimicking certain chromosome junctions of lymphomas were shown to be highly tumorigenic when inserted into the mouse germline. Nevertheless, the mechanism by which an immunoglobulin locus activates the oncogene remains largely an enigma, (...) particularly in those cases where the two loci remain at some distance. (shrink)

I discuss the two different responses from the angiosperms to the specific molecular mechanisms of the tumor-inducing agent contained in the bacteriumAgrobacterium tumefaciens. This is done in terms of the collective variables for expressing genetic response to a continuously varying supply of energy from metabolic pathways. We are led to the conjecture that the expression of the recessive oncogenes may not be restricted to humans (retinoblastoma and osteosarcoma), but may also occur in plants (crown gall), and be expressed through a (...) heat-shock. (shrink)

Ductin is the highest conserved membrane protein yet found in eukaryotes. It is multifunctional, being the subunit c or proteolipid component of the vacuolar H+‐ATPase and at the same time the protein component of a form of gap junction in metazoan animals. Analysis of its structure shows it to be a tandem repeat of two 8‐kDa domains derived from the subunit c of the F0 proton pore from the F1F0 ATPase. Each domain contains two transmembrane α‐helices, which together may form (...) a four‐helix bundle. In both the V‐ATPase and gap junction channel, ductin is probably arranged as a hexamer of subunits forming a central channel of gap junction‐like proportions. The two functions appear to be seggregated by ductin having two orientations in the bilayer. Ductin is also the major component of the mediatophore, a protein complex which may aid in the release of neurotransmitters across the pre‐synaptic membrane. It is also a target for a class of poorly understood viral polypeptides. These polypeptides are small and highly hydrophobic and some have oncogenic activity. Ductin thus appears to be at the crossroads of a number of biological processes. (shrink)

Despite the spectacular contributions to knowledge made by molecular biology during the last half century, cancer research has not delivered an agreed explanation of how malignant tumours originate. The models assiduously investigated in molecular terms largely reflect waves of fashion, and time has revealed their inadequacy: cancer is (1) not caused by the direct action of oncogenes, (2) not fully explained by the impairment of tumour suppressor genes, (3) not set in motion by mutations controlling the cell cycle, (4) not (...) governed by the dependence of malignant tumours on an adequate blood supply and (5) not triggered by a failure of programmed cell death. But there is now strong evidence that cancers may have their origin in mutations that block the execution of critical steps in the process of normal differentiation. Cancer, thus seen, is not initially a disease of cell multiplication, but a disease of differentiation. The evidence for this point of view should now be explored. BioEssays 27:833–838, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Recent studies indicate that plakoglobin may have a similar function to that of β-catenin within the Wnt signaling pathway. β-catenin is known to be an oncogene in many forms of human cancer, following acquisition of stabilizing mutations in amino terminal sequences. Kolligs1 and coworkers show, however, that unlike β-catenin, plakoglobin induces neoplastic transformation of rat epithelial cells in the absence of such stabilizing mutations. Cellular transformation by plakoglobin also appears to be distinct from that of β-catenin in that it (...) requires activation of the proto-oncogene c-myc. Surprisingly, c-myc is activated more efficiently by plakoglobin than β-catenin, despite its previous identification as a target of Tcf/β-catenin.2 In contrast, a synthetic Tcf reporter gene is activated to a much greater extent by β-catenin than plakoglobin. Plakoglobin and β-catenin may therefore have different roles in Wnt signaling and cancer, which reflect their differential effects on target gene activity. BioEssays 22:961–965, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Oncogenesis is manifested as uncontrolled cellular proliferation and in some situations a failure of normal differentiation in the transformed cell. This has led to speculation that the normal role of proto‐oncogenes during development may be to mediate the relationship between proliferation and differentiation. The advent of gene targeting in ES cells allows the role oncogenes in development to be tested directly. Two recent studies have examined the phenotype of N‐myc mutant mice generated by gene targeting(1,2). In both reports, the mutation (...) is an embryonic lethal at 11.5 days of gestation confirming a critical role for this proto‐oncogene in development and the inability of other members of the myc family to substitute functionally for N‐myc. Although the phenotypes are similar in general outline, the two reports differ in the specifics of the morphological and histological abnormalities identified. The disparity may result from the mutation created, the genetic background of the mutant mice or the criteria used to determine abnormalities. Assuredly, there is valuable information to be gained about N‐myc function from these mutant mice. However, these reports make it clear that morphological and histological abnormalities in N‐myc mutant mice serve as a starting point rather than as an endpoint. The challenge now is to link the defect at the cellular level to the abnormalities at the physiological level. (shrink)

Hirschsprung disease and the multiple endocrine neoplasia type 2 syndromes are hereditary disorders related to the abnormal migration, proliferation or survival of neural crest cells and their derivatives. Hirschsprung disease is a frequent disorder of the enteric nervous system, resulting in intestinal obstruction. The multiple endocrine neoplasia type 2 syndromes predispose to cancers of neural crest derivatives. Both diseases are associated with heterozygous mutations in the RET proto‐oncogene. RET encodes a transmembrane receptor tyrosine kinase expressed in neural crest lineages (...) and whose ligand, glial‐cell‐line‐derived neurotrophic factor, has been very recently identified. In vitro expression studies demonstrate that while Hirschsprung disease mutations result in loss of function of the mutant RET tyrosine kinase, multiple endocrine neoplasia type 2 mutations lead to its constitutive activation. Thus, the two ‘faces’ of RET, gain of function and loss of function, each lead to a different syndrome, respectively: multiple endocrine neoplasia type 2, a cancer syndrome, or Hirschsprung disease, a developmental defect. (shrink)

Mutations in enhancer‐associated chromatin‐modifying components and genomic alterations in non‐coding regions of the genome occur frequently in cancer, and other diseases pointing to the importance of enhancer fidelity to ensure proper tissue homeostasis. In this review, I will use specific examples to discuss how mutations in chromatin‐modifying factors might affect enhancer activity of disease‐relevant genes. I will then consider direct evidence from single nucleotide polymorphisms, small insertions, or deletions but also larger genomic rearrangements such as duplications, deletions, translocations, and inversions (...) of specific enhancers to demonstrate how they have the ability to impact enhancer activity of disease genes including oncogenes and tumor suppressor genes. Considering that the scientific community only fairly recently has begun to focus its attention on “enhancer malfunction” in disease, I propose that multiple new enhancer‐regulated and disease‐relevant processes will be uncovered in the near future that will constitute the mechanistic basis for novel therapeutic avenues. (shrink)

Mutations in enhancer‐associated chromatin‐modifying components and genomic alterations in non‐coding regions of the genome occur frequently in cancer, and other diseases pointing to the importance of enhancer fidelity to ensure proper tissue homeostasis. In this review, I will use specific examples to discuss how mutations in chromatin‐modifying factors might affect enhancer activity of disease‐relevant genes. I will then consider direct evidence from single nucleotide polymorphisms, small insertions, or deletions but also larger genomic rearrangements such as duplications, deletions, translocations, and inversions (...) of specific enhancers to demonstrate how they have the ability to impact enhancer activity of disease genes including oncogenes and tumor suppressor genes. Considering that the scientific community only fairly recently has begun to focus its attention on “enhancer malfunction” in disease, I propose that multiple new enhancer‐regulated and disease‐relevant processes will be uncovered in the near future that will constitute the mechanistic basis for novel therapeutic avenues. (shrink)

Alterations in the expression of certain genes or in their products can render benign tumor cells metastatic. Experimentally this has been quickly performed by transferring dominantly acting oncogenes such as c‐H‐rasEJ into susceptible cells, but in vivo such a rapid qualitative change in a dominantly acting oncogene occurs only rarely, and progression to highly metastatic phenotypes is thought to occur through a slow stepwise process. Such slow changes can be reversible and need not involve known dominantly acting oncogenes, consistent (...) with clinical observations. An important element of the natural progression of tumors to malignancy may be their ability to circumvent microenvironmental controls that regulate growth and cellular diversity and to evolve into heterogeneous phenotypes, a process that appears to involve mainly quantitative changes in gene expression but which can be rapidly stimulated in cell culture by the introduction of a dominantly acting oncogene. It is proposed that the highly malignant cells that have slowly evolved in vivo with only a few qualitative gene changes have undergone extensive cycles of diversification and accumulation of quantitative changes in the expression of genes that encode products that are related to malignancy and metastasis. Thus, highly malignant cellular phenotypes can arise quickly through specific qualitative changes in critical controlling genes or more slowly by less critical qualitative genetic changes, coupled with cellular diversification and accumulation of quantitative changes in gene expression. (shrink)