Documented interactions among members of the Myc superfamily support a yin-yang model for the regulation of Myc-responsive genes in which transactivation-competent Myc-Max heterodimers are opposed by repressive Mxi1-Max or Mad-Max complexes. Analysis of mouse mxi1 has led to the identification of two mxi1 transcript forms possessing open reading frames that differ in their capacity to encode a short amino-terminal alpha-helical domain. The presence of this segment dramatically augments the suppressive potential of Mxi1 and allows for association with a mammalian protein that is structurally homologous to the yeast transcriptional repressor SIN3. These findings provide a mechanistic basis for the antagonistic actions of Mxi1 on Myc activity that appears to be mediated in part through the recruitment of a putative transcriptional repressor.
With exciting new NASA plans for a sustainable return to the moon, astronauts will once again leave Earth's protective magnetosphere only to endure higher levels of radiation from galactic cosmic radiation (GCR) and the possibility of a large solar particle event (SPE). Gateway, lunar landers, and surface habitats will be designed to protect crew against SPEs with vehicle optimization, storm shelter concepts, and/or active dosimetry; however, the ever penetrating GCR will continue to pose the most significant health risks especially as lunar missions increase in duration and as NASA sets its aspirations on Mars. The primary risks of concern include carcinogenesis, central nervous system (CNS) effects resulting in potential in-mission cognitive or behavioral impairment and/or late neurological disorders, degenerative tissue effects including circulatory and heart disease, as well as potential immune system decrements impacting multiple aspects of crew health. Characterization and mitigation of these risks requires a significant reduction in the large biological uncertainties of chronic (low-dose rate) heavy-ion exposures and the validation of countermeasures in a relevant space environment. Historically, most research on understanding space radiation-induced health risks has been performed using acute exposures of monoenergetic single-ion beams. However, the space radiation environment consists of a wide variety of ion species over a broad energy range. Using the fast beam switching and controls systems technology recently developed at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory, a new era in radiobiological research is possible. NASA has developed the "GCR Simulator" to generate a spectrum of ion beams that approximates the primary and secondary GCR field experienced at human organ locations within a deepspace vehicle. The majority of the dose is delivered from protons (approximately 65%-75%) and helium ions (approximately 10%-20%) with heavier ions (Z � 3) contributing the remainder. The GCR simulator exposes state-of-the art cellular and animal model systems to 33 sequential beams including 4 proton energies plus degrader, 4 helium energies plus degrader, and the 5 heavy ions of C, O, Si, Ti, and Fe. A polyethylene degrader system is used with the 100 MeV/n H and He beams to provide a nearly continuous distribution of lowenergy particles. A 500 mGy exposure, delivering doses from each of the 33 beams, requires approximately 75 minutes. To more closely simulate the low-dose rates found in
Studies of adenovirus EIA oncoprotein mutants suggest that the association of ElA with the retinoblastoma protein (pRB) is necessary for ElA-mediated transformation. Mutational analysis of ELA indicates that two regions of pRB are required for ELA to form stable complexes with the retinoblastoma protein. In addition to pRB binding, these regions are necessary for ElA association with several other cellular proteins, including p130, p107, cycin A, and p33cdk2. Here we show that short synthetic peptides containing the pRB-binding sequences of E1A are sufficient for interaction with p107, cyclin A, and p130. The E7 protein of human papillomavirus type 16 contains an element that binds to pRB and appears to be functionally homologous to the ElA sequences. Peptides containing this region of the E7 protein were able to interact with p107, cyclin A, and p130 in addition to pRB. These findings suggest that the common mechanism of transformation used by these viral oncogenes involves their association with a set of polypeptides. The adenovirus ElA oncoprotein has pleiotropic effects on cell proliferation. These changes appear to be mediated, at least in part, by the association of ElA with several cellular proteins. Stable protein complexes are readily detected in adenovirus-infected or-transformed cells (29, 58), and several genetic studies have correlated the ability of ElA mutants to bind to cellular proteins with their activities in transformation assays, cell immortalization, or the stimulation of host cell DNA synthesis after viral infection (19, 33, 36, 53, 57). To date the binding sites of six cellular proteins have been mapped to the region of ElA with transforming activity. These are the retinoblastoma protein, pRB, and a related protein, p107 (22, 56); cyclin A and a cyclin A-associated kinase, p33cdIa (24-26, 55); and two additional proteins, p130 and p300 (26, 57). Analysis of the protein-binding properties of various ElA mutants has identified short segments of ElA that are essential for stable association with several of these cellular proteins. Deletion of amino acids 120 to 127 largely inhibits the formation of ElA complexes with at least five polypeptides, pRB, p107, p130, cyclin A, and p33Cdk2 (25, 26, 57). Similarly, ElA deletions that include amino acids 30 to 60 produce ElA mutants that have severely impaired binding to pRB, p130, cyclin A, and p33cdk2 (25, 26, 57). The binding site of p300 appears to be distinct from that of these other proteins (57); it lies within the amino-terminal 49 amino acids of ElA (42). The early proteins of other small DNA tumor viruses also bind to pRB (11, 14, 17, 46). For the large T antigens of simian virus 40 (SV40) and polyomavirus and the E7 proteins of human papillomavirus type 16 (HPV-16), mutagenesis of the pRB-binding sequences reveals a correlation between the pRB-binding properties and the cell immortalization or transforming properties of these oncoproteins (11, 30, 41, 46-48). The similarities between these viral proteins suggests that these oncogenes may be...
Most accelerator-based space radiation experiments have been performed with single ion beams at fixed energies. However, the space radiation environment consists of a wide variety of ion species with a continuous range of energies. Due to recent developments in beam switching technology implemented at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), it is now possible to rapidly switch ion species and energies, allowing for the possibility to more realistically simulate the actual radiation environment found in space. The present paper discusses a variety of issues related to implementation of galactic cosmic ray (GCR) simulation at NSRL, especially for experiments in radiobiology. Advantages and disadvantages of different approaches to developing a GCR simulator are presented. In addition, issues common to both GCR simulation and single beam experiments are compared to issues unique to GCR simulation studies. A set of conclusions is presented as well as a discussion of the technical implementation of GCR simulation.
Two regions near the amino terminus of the adenovirus E1A protein, which were first identified by sequence conservation among various adenovirus serotypes, have been shown by genetic studies to be essential for E1A-mediated transformation. These same regions are also required for interaction with a number of cellular proteins, including the retinoblastoma protein (pRB). Using synthetic peptides corresponding to portions of these conserved regions, we show that each region can bind independently to pRB. These interactions were observed in both competition and binding assays. In both types of assay, region 2 peptides (E1A amino acids 115 to 132) bound pRB with higher affinity than did region 1 peptides (E1A amino acids 37 to 54), while a peptide combining region 1 and 2 sequences consistently provided the highest-affinity interaction. Cross-blocking experiments using region 1 peptides and region 2 peptides suggested that these two regions of E1A make distinct contacts with pRB. These data support the notion that the pRB-binding domain of E1A contains at least two functional elements.
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