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OPEN ACCESS PLUS
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Contents
Pp. 446 - 458
S. Ke, W. Wang, X. Qiu, F. Zhang, J. T. Yustein, A. G. Cameron, S. Zhang, D. Yu, C. Zou, X. Gao, J. Lin, S. Yallampalli and M. Li
[Open Access Plus] |
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Breast cancer is a heterogenetic tumor at the cellular level with multiple factors and components. The inconsistent expression of molecular markers during disease progression reduces the accuracy of diagnosis and efficacy of target-specific therapy. Single target-specific imaging agents can only provide limited tumor information at one time point. In contrast, multiple target-specific imaging agents can increase the accuracy of diagnosis. The aim of this study was to demonstrate the ability of multi-agent imaging to discriminate such differences in single tumor. Mice bearing human cancer cell xenografts were tested to determine individual differences under optimal experimental conditions. Neovasculature agent (RGD peptide), tumor stromal agent (matrix metalloproteinase), and tumor cell markers (epidermal growth factor, Her-2, interleukin 11) imaging agents were labeled with reporters. 18F-Fluorodeoxyglucose was used to evaluate the tumor glucose status. Optical, X-ray, positron emission tomography, and computer tomography imaging modalities were used to determine tumor characteristics. Tumor size and imaging data demonstrated that individual differences exist under optimal experimental conditions. The target-specific agents used in the study bind to human breast cancer cell lines in vitro and xenografts in vivo. The pattern of binding corresponds to that of tumor markers. Multi-agent imaging had complementary effects in tumor detection. Multiple noninvasive imaging agents and modalities are complementary in the interrogation of unique biological information from each individual tumor. Such multi-agent approaches provide methods to study several disease components simultaneously. In addition, the imaging results provide information on disease status at the molecular level.
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Pp. 205 - 219
J. Montalvo, C. Spencer, A. Hackathorn, K. Masterjohn, A. Perkins, C. Doty, A. Arumugam, P. P. Ongusaha, R. Lakshmanaswamy, J. K. Liao, D. C. Mitchell and B. A. Bryan
[Open Access Plus] |
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The serine/threonine protein kinase paralogs ROCK1 & 2 have been implicated as essential modulators of angiogenesis; however their paralog-specific roles in endothelial function are unknown. shRNA knockdown of ROCK1 or 2 in endothelial cells resulted in a significant disruption of in vitro capillary network formation, cell polarization, and cell migration compared to cells harboring non-targeting control shRNA plasmids. Knockdowns led to alterations in cytoskeletal dynamics due to ROCK1 & 2-mediated reductions in actin isoform expression, and ROCK2-specific reduction in myosin phosphatase and cofilin phosphorylation. Knockdowns enhanced cell survival and led to ROCK1 & 2-mediated reduction in caspase 6 and 9 cleavage, and a ROCK2-specific reduction in caspase 3 cleavage. Microarray analysis of ROCK knockdown lines revealed overlapping and unique control of global transcription by the paralogs, and a reduction in the transcriptional regulation of just under 50% of VEGF responsive genes. Finally, paralog knockdown in xenograft angiosarcoma tumors resulted in a significant reduction in tumor formation. Our data reveals that ROCK1 & 2 exhibit overlapping and unique roles in normal and dysfunctional endothelial cells, that alterations in cytoskeletal dynamics are capable of overriding mitogen activated transcription, and that therapeutic targeting of ROCK signaling may have profound impacts for targeting angiogenesis.
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Pp. 13 - 23
L. Lasagni, E. Lazzeri, S. J. Shankland, H.-J. Anders and P. Romagnani
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Podocyte loss plays a key role in the progression of glomerular disorders towards glomerulosclerosis and chronic kidney disease. Podocytes form unique cytoplasmic extensions, foot processes, which attach to the outer surface of the glomerular basement membrane and interdigitate with neighboring podocytes to form the slit diaphragm. Maintaining these sophisticated structural elements requires an intricate actin cytoskeleton. Genetic, mechanic, and immunologic or toxic forms of podocyte injury can cause podocyte loss, which causes glomerular filtration barrier dysfunction, leading to proteinuria. Cell migration and cell division are two processes that require a rearrangement of the actin cytoskeleton; this rearrangement would disrupt the podocyte foot processes, therefore, podocytes have a limited capacity to divide or migrate. Indeed, all cells need to rearrange their actin cytoskeleton to assemble a correct mitotic spindle and to complete mitosis. Podocytes, even when being forced to bypass cell cycle checkpoints to initiate DNA synthesis and chromosome segregation, cannot complete cytokinesis efficiently and thus usually generate aneuploid podocytes. Such aneuploid podocytes rapidly detach and die, a process referred to as mitotic catastrophe. Thus, detached or dead podocytes cannot be adequately replaced by the proliferation of adjacent podocytes. However, even glomerular disorders with severe podocyte injury can undergo regression and remission, suggesting alternative mechanisms to compensate for podocyte loss, such as podocyte hypertrophy or podocyte regeneration from resident renal progenitor cells. Together, mitosis of the terminally differentiated podocyte rather accelerates podocyte loss and therefore glomerulosclerosis. Finding ways to enhance podocyte regeneration from other sources remains a challenge goal to improve the treatment of chronic kidney disease in the future.
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Pp. 944 - 951
S. Ke, F. Zhang, W. Wang, X. Qiu, J. Lin, A. G. Cameron, C. Zou, X. Gao, C. Zou, V. F. Zhu and M. Li
[Open Access Plus] |
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Liver cancer is the fifth most common cause of cancer deaths worldwide. Noninvasive diagnosis is difficult and the disease heterogeneity reduces the accuracy of pathological assays. Improvement in diagnostic imaging of specific molecular disease markers has provided hope for accurate and early noninvasive detection of liver cancer. However, all current imaging technologies, including ultrasonography, computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging, are not specific targets for detection of liver cancer. The aim of this study was to test the feasibility of injecting a cocktail of specific molecular imaging agents to noninvasively image liver cancer. The target-specific cocktail contained agents for imaging the neovasculature (RGD peptide), matrix metalloproteinase (MMP), and glucose transport (18F-fluorodeoxyglucose [18F-FDG]). Imaging studies were performed in liver cancer cells and xenograft models. The distribution of MMP at the intracellular level was imaged by confocal microscopy. RGD, MMP, and 18F-FDG were imaged on tumor-bearing mice using PET, CT, X-ray, and multi-wavelength optical imaging modalities. Image data demonstrated that each agent bound to a specific disease target component. The same liver cancer xenograft contained multiple disease markers. Those disease markers were heterogenetically distributed in the same tumor nodule. The molecular imaging agents had different distributions in the whole body and inside the tumor nodule. All target-specific agents yielded high tumor-to-background ratios after injection. In conclusion, target-specific molecular imaging agents can be used to study liver cancer in vitro and in vivo. Noninvasive multimodal/multi-target-specific molecular imaging agents could provide tools to simultaneously study multiple liver cancer components.
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Pp. 772 - 787
P. T. Tran, R. K. Hales, J. Zeng, K. Aziz, T. Salih, R. P. Gajula, S. Chettiar, N. Gandhi, A. T. Wild, R. Kumar, J. M. Herman, D. Y. Song and T. L. DeWeese
[Open Access Plus] |
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Prostate cancer is the most common cancer and second leading cause of cancer deaths among men in the United States. Most men have localized disease diagnosed following an elevated serum prostate specific antigen test for cancer screening purposes. Standard treatment options consist of surgery or definitive radiation therapy directed by clinical factors that are organized into risk stratification groups. Current clinical risk stratification systems are still insufficient to differentiate lethal from indolent disease. Similarly, a subset of men in poor risk groups need to be identified for more aggressive treatment and enrollment into clinical trials. Furthermore, these clinical tools are very limited in revealing information about the biologic pathways driving these different disease phenotypes and do not offer insights for novel treatments which are needed in men with poor-risk disease. We believe molecular biomarkers may serve to bridge these inadequacies of traditional clinical factors opening the door for personalized treatment approaches that would allow tailoring of treatment options to maximize therapeutic outcome. We review the current state of prognostic and predictive tissuebased molecular biomarkers which can be used to direct localized prostate cancer treatment decisions, specifically those implicated with definitive and salvage radiation therapy.
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Pp. 391 - 400
P. V. Luoma
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Atherosclerotic vascular disease, diabetes mellitus (DM) and dementia are major global health problems. Both endogenous and exogenous factors activate genes functioning in biological processes. This review article focuses on gene-activation mechanisms that regress atherosclerosis, eliminate DM type 2 (DM2), and prevent cognitive decline and dementia. Gene-activating compounds upregulating functions of liver endoplasmic reticulum (ER) and affecting lipid and protein metabolism, increase ER size through membrane synthesis, and produce an antiatherogenic plasma lipoprotein profile. Numerous gene-activators regress atherosclerosis and reduce the occurrence of atherosclerotic disease. The gene-activators increase glucose disposal rate and insulin sensitivity and, by restoring normal glucose and insulin levels, remove metabolic syndrome and DM2. Patients with DM2 show an improvement of plasma lipoprotein profile and glucose tolerance together with increase in liver phospholipid (PL) and cytochrome (CYP) P450. The gene-activating compounds induce hepatic protein and PL synthesis, and upregulate enzymes including CYPs and glucokinase, nuclear receptors, apolipoproteins and ABC (ATPbinding cassette) transporters. They induce reparation of ER structures and eliminate consequences of ER stress. Healthy living habits activate mechanisms that maintain high levels of HDL and apolipoprotein AI, promote health, and prevent cognitive decline and dementia. Agonists of liver X receptor (LXR) reduce amyloid in brain plaques and improve cognitive performance in mouse models of Alzheimer's disease. The gene activation increases the capacity to withstand cellular stress and to repair cellular damage and increases life span. Life free of major health problems and in good cognitive health promotes well-being and living a long and active life.
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Pp. 304 - 316
R. A. McGregor and M. S. Choi
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Worldwide obesity is a growing health problem, associated with increased risk of chronic disease. Understanding the molecular basis of adipogenesis and fat cell development in obesity is essential to identify new biomarkers and therapeutic targets for the development of anti-obesity drugs. microRNAs (miRNAs) appear to play regulatory roles in many biological processes associated with obesity, including adipocyte differentiation, insulin action and fat metabolism. Recent studies show miRNAs are dysregulated in obese adipose tissue. During adipogenesis miRNAs can accelerate or inhibit adipocyte differentiation and hence regulate fat cell development. In addition miRNAs may regulate adipogenic lineage commitment in multipotent stem cells and hence govern fat cell numbers. Recent findings suggest miR-519d may be associated with human obesity, but larger case-control studies are needed. Few miRNA targets have been experimentally validated in adipocytes but interestingly both miR-27 and miR-519d target PPAR family members, which are well established regulators of fat cell development. In this review recent advances in our understanding of the role of miRNAs in fat cell development and obesity are discussed. The potential of miRNA based therapeutics targeting obesity is highlighted as well as recommendations for future research which could lead to a breakthrough in the treatment of obesity.
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Pp. 246 - 254
P. A. McCombe and R. D. Henderson
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Amyotrophic lateral sclerosis (ALS) is a severe progressive neurodegenerative disease. The cause is unknown, but genetic abnormalities have been identified in subjects with familial ALS and also in subjects with sporadic ALS. Environmental factors such as occupational exposure have been shown to be risk factors for the development of ALS. Patients differ in their clinical features and differ in the clinical course of disease. Immune abnormalities have been found in the central nervous system by pathological studies and also in the blood and CSF of subjects with ALS. Inflammation and immune abnormalities are also found in animals with a model of ALS due to mutations in the SOD1 gene. Previously it has been considered that immune abnormalities might contribute to the pathogenesis of disease. However more recently it has become apparent that an immune response can occur as a response to damage to the nervous system and this can be protective.
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Pp. 93 - 109
T. M. Witkos, E. Koscianska and W. J. Krzyzosiak
[Open Access Plus] |
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microRNAs (miRNAs) are endogenous non-coding RNAs that control gene expression at the posttranscriptional level. These small regulatory molecules play a key role in the majority of biological processes and their expression is also tightly regulated. Both the deregulation of genes controlled by miRNAs and the altered miRNA expression have been linked to many disorders, including cancer, cardiovascular, metabolic and neurodegenerative diseases. Therefore, it is of particular interest to reliably predict potential miRNA targets which might be involved in these diseases. However, interactions between miRNAs and their targets are complex and very often there are numerous putative miRNA recognition sites in mRNAs. Many miRNA targets have been computationally predicted but only a limited number of these were experimentally validated. Although a variety of miRNA target prediction algorithms are available, results of their application are often inconsistent. Hence, finding a functional miRNA target is still a challenging task. In this review, currently available and frequently used computational tools for miRNA target prediction, i.e., PicTar, TargetScan, DIANA-microT, miRanda, rna22 and PITA are outlined and various practical aspects of miRNA target analysis are extensively discussed. Moreover, the performance of three algorithms (PicTar, TargetScan and DIANAmicroT) is both demonstrated and evaluated by performing an in-depth analysis of miRNA interactions with mRNAs derived from genes triggering hereditary neurological disorders known as trinucleotide repeat expansion diseases (TREDs), such as Huntingtons disease (HD), a number of spinocerebellar ataxias (SCAs), and myotonic dystrophy type 1 (DM1).
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Pp. 640 - 652
R. Seigneuric, L. Markey, D. S.A. Nuyten, C. Dubernet, C. T.A. Evelo, E. Finot and C. Garrido
[Open Access Plus] |
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Scientific advances have significantly improved the practice of medicine by providing objective and quantitative means for exploring the human body and disease states. These innovative technologies have already profoundly improved disease detection, imaging, treatment and patient follow-up. Todays analytical limits are at the nanoscale level (one-billionth of a meter) enabling a detailed exploration at the level of DNA, RNA, proteins and metabolites which are in fact nano-objects. This translational review aims at integrating some recent advances from micro- and nano-technologies with high potential for improving daily oncology practice.
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Pp. 727 - 740
P. Collini, M. Noursadeghi, I. Sabroe, R. F. Miller and D. H. Dockrell
[Open Access Plus] |
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HIV-1 can establish both long lived and productive infection of macrophages (M) but circulating monocytes are less permissive to infection. Multiple studies have identified extensive changes to monocyte and M phenotype, differentiation or function. These include alterations in Toll-like receptor signaling and resultant changes to cytokine responses, specific defects in phagocytosis and microbial killing and modulation of apoptotic responses, all of which may perturb the important role of these cells in innate immunity. Interpretation of contradictory data however, is complicated by the use of different experimental models and many of the reported effects may be an indirect consequence of HIV-1 infection that result from exposure to viral products or from disruption of cellular and cytokine networks in the immune system, rather than the direct consequence of productive HIV-1 infection. Future research should focus on refining experimental models and on elucidating the physiological mechanisms of monocyte/ M dysfunction during HIV-1 infection.
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Pp. 430 - 439
H. Matthes, W.E. Friedel, P.R. Bock and K.S. Zanker
[Open Access Plus] |
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Mistletoe is often used as complementary therapy in oncology. The anti-tumor effects of mistletoe (Iscador®) are well documented in-vitro in respect to inhibition of cell proliferation, induction of apoptosis, segmental activation of immune competent cells and trapping of chemotherapeutic drugs within cancer cells by modulating the inhibitory potential of P-glycoprotein (P-gp)-mediated transport of cell toxifying substances (cytotoxic drugs). However, the clinical activity of mistletoe treatment remains still controversial. Implementation of mistletoe therapy as supportive care into anti-cancer programs should be based on the best evidence and must continually be evaluated to ensure safety, efficacy, collection of new data, and cost-effectiveness. Useful domains that can be evaluated include symptom control, adherence to conventional treatment protocols, quality of life, individual outcome and potential advantages of a whole-system health approach. Here we report the results of a multicenter, controlled, retrospective and observational pharmacoepidemiological study in patients suffering from a pancreatic carcinoma. After surgery the patients were treated by adjuvant chemotherapy with gemcitabine supported by Iscador®, or with gemcitabine alone, or any other best of care, but not including Iscador®. Using a novel methodological pharmaco-epidemiological design and statistical approach it could be shown that Iscador® offers benefits - symptom control, overall survival - as supportive care within gemcitabine protocols of patients with surgically resected pancreatic carcinoma.
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Pp. 826 - 835
L. Kupfer, W. Hinrichs and M. H. Groschup
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The crucial event in the development of transmissible spongiform encephalopathies (TSEs) is the conformational change of a host-encoded membrane protein - the cellular PrPC - into a disease associated, fibril-forming isoform PrPSc. This conformational transition from the α8-helix-rich cellular form into the mainly β- sheet containing counterpart initiates an autocatalytic reaction which leads to the accumulation of amyloid fibrils in the central nervous system (CNS) and to neurodegeneration, a hallmark of TSEs. The exact molecular mechanisms which lead to the conformational change are still unknown. It also remains to be brought to light how a polypeptide chain can adopt at least two stable conformations. This review focuses on structural aspects of the prion protein with regard to protein-protein interactions and the initiation of prion protein misfolding. It therefore highlights parts of the protein which might play a notable role in the conformational transition from PrPC to PrPSc and consequently in inducing a fatal chain reaction of protein misfolding. Furthermore, features of different proteins, which are able to adopt insoluble fibrillar states under certain circumstances, are compared to PrP in an attempt to understand the unique characteristics of prion diseases.
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Pp. 497 - 509
Helen M. Marriott, Timothy J. Mitchell and David H. Dockrell
[Open Access Plus] |
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The cholesterol-dependent cytolysins are pore-forming toxins. Pneumolysin is the cytolysin produced by Streptococcus pneumoniae and is a key virulence factor. The protein contains 471 amino acids and four structural domains. Binding to cholesterol is followed by oligomerization and membrane pore formation. Pneumolysin also activates the classical pathway of complement. Mutational analysis of the toxin and knowledge of sequence variation in outbreak strains suggests that additional activities of biologic importance exist. Pneumolysin activates a large number of genes, some by epigenetic modification, in eukaryotic cells and multiple signal transduction pathways. Cytolytic effects contribute to lung injury and neuronal damage while proinflammatory effects compound tissue damage. Nevertheless pneumolysin is a focal point of the immune response to pneumococci. Toll-like receptor 4-mediated recognition, osmosensing and T-cell responses to pneumolysin have been identified. In some animal models mutants that lack pneumolysin are associated with impaired bacterial clearance. Pneumolysin, which itself may induce apoptosis in neurones and other cells can activate host-mediated apoptosis in macrophages enhancing clearance. Disease pathogenesis, which has traditionally focused on the harmful effects of the toxin, increasingly recognises that a precarious balance between limited host responses to pneumolysin and either excessive immune responses or toxin-mediated subversion of host immunity exists.
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Pp. 138 - 147
Gordon C. Shore and Matthew R. Warr
[Open Access Plus] |
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Accumulating evidence suggests that Mcl-1 plays a critical pro-survival role in the development and maintenance of both normal and malignant tissues. Regulation of Mcl-1 expression occurs at multiple levels, allowing for either the rapid induction or elimination of the protein in response to different cellular events. This suggests that Mcl-1 can play an early role in response to signals directing either cell survival or cell death. Deregulation of pathways regulating Mcl-1 that result in its over-expression likely contribute to a cells inability to properly respond to death signals possibly leading to cell immortalization and tumorigenic conversion. Correspondingly, Mcl-1 has been shown to be up-regulated in numerous hematological and solid tumor malignancies. Moreover, this up-regulation appears to be a factor in the resistance of some cancer types to conventional cancer therapies. Mechanisms that abrogate the pro-survival function of Mcl-1 either by diminishing its levels or inactivating its functional BH3 groove have shown promise for the combinational treatment with existing cancer therapies and as single agents in certain malignancies. Here we review the various pathways that regulate Mcl-1 expression and describe agents that are currently under development to modulate Mcl-1 activity for therapeutic benefit in oncology.
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Pp. 759 - 781
Marek Pacal and Rod Bremner
[Open Access Plus] |
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The RB gene was discovered 20 years ago because of its role in the childhood eye cancer retinoblastoma. However, surprisingly little progress was made in defining the role of RB protein in the retina. In the last two years, new models exploiting conditional deletion of the mouse Rb gene have altered this picture radically. These models provide insight into the first Rb function, the cell of origin of retinoblastoma, the window during which Rb acts, distinct cell-specific defenses against Rb loss, the number and type of post-Rb lesions required for transformation, why pediatric tumors exist, the controversial role of the p53 pathway in retinoblastoma, and the reason why the disease is virtually unique to humans. Two years have dramatically improved our understanding of Rb function in the tissue that gave us this important tumor suppressor.
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Pp. 739 - 748
James DeGregori and David G. Johnson
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Since the discovery almost fifteen years ago that E2F transcription factors are key targets of the retinoblastoma protein (RB), studies of the E2F family have uncovered critical roles in the control of transcription, cell cycle and apoptosis. E2F proteins are encoded by at least eight genes, E2F1 through E2F8. While specific roles for individual E2Fs in mediating the effects of RB loss are emerging, it is also becoming clear that there are no simple divisions of labor among the E2F family. Instead, an individual E2F can function to activate or repress transcription, promote or impede cell cycle progression and enhance or inhibit cell death, dependent on the cellular context. While functional redundancy among E2Fs and the striking influences of cellular context on the effects of E2F loss or gain of function have prevented a simple delineation of unique functions within the E2F family, these complexities undoubtedly reflect the extensive regulation and importance of this transcription factor family.
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Pp. 731 - 738
David G. Johnson and James DeGregori
[Open Access Plus] |
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Deregulation of E2F transcriptional activity as a result of alterations in the p16INK4a-cyclin D1-Rb pathway is a hallmark of human cancer. E2F is a family of related factors that controls the expression of genes important for cell cycle progression as well as other processes such as apoptosis, DNA repair, and differentiation. Some E2F family members are associated with the activation of transcription and the promotion of proliferation while others are implicated in repressing transcription and inhibiting cell growth. It is now becoming clear however, that this view of the E2F family is overly simplistic and that the role of a given E2F in regulating transcription and cell growth is highly dependent on context. This complexity is also evident when analyzing how perturbations in E2F modulate tumor development. As expected, some E2F family members are found to be critical for mediating the oncogenic effects of Rb loss. On the other hand, several E2Fs have tumor suppressive properties in mouse models and this appears to be reflected in some human cancers with decreased E2F expression. Surprisingly, tumor suppressive activity is not associated with the repressor E2Fs but instead is associated with the same E2Fs shown to have oncogenic activities. For example, deregulated E2F1 expression can either promote or inhibit tumorigenesis depending on the nature of the other oncogenic mutations that are present. Thus, the ability of some E2F family members to behave as both oncogene and tumor suppressor gene can be reconciled by putting E2F into context.
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