Independent regulation of P53 stabilisation and activation after Rb deletion in primary epithelial cells

We have previously reported that deletion of the retinoblastoma gene Rb leads to rapid but transient p53 stabilisation. We investigated here the pathways involved. We show that upon Rb-deletion dysregulated E2F activates p19(ARF) expression that localises in the nucleoli. There it interacts with MDM2, leading to P53 stabilisation. At the same time, ATR is activated, activating CHK1 that may phosphorylate P53 but also contribute to inhibition of MnSOD expression leading to accumulation of ROS (reactive oxygen species) and subsequent DNA injury, which in turn maintains ATR/CHK1 activated. However, from 72 h after Rb deletion, NPM interacts with P19ARF and concomitantly the interaction between p19(ARF) and MDM2 decreases leading to a return to P53 degradation. This occurs despite the persistence of the DNA damage response pathways. We therefore observe in primary cells not subjected to exogenous gene expression or exogenous DNA damaging treatment, activation of 2 concomitant pathways of activation of P53 that are dealt with in independent manner: an oncogenic pathway with rapid activation of ARF which is 'switched off' downstream of p19(ARF) activation after 72 h of induction and a DNA damage response pathway keeping a low level of transcriptionally active P53 sufficient to deal with a physiological elevation of oxidative DNA injury. A possible connection between the two pathways is discussed.Publisher PDFPeer reviewe

Deficiency of G1 regulators P53, P21Cip1 and/or pRb decreases hepatocyte sensitivity to TGFbeta cell cycle arrest

TGFbeta is critical to control hepatocyte proliferation by inducing G1-growth arrest through multiple pathways leading to inhibition of E2F transcription activity. The retinoblastoma protein pRb is a key controller of E2F activity and G1/S transition which can be inhibited in viral hepatitis. It is not known whether the impairment of pRb would alter the growth inhibitory potential of TGFbeta in disease. We asked how Rb-deficiency would affect responses to TGFbeta-induced cell cycle arrest.Publisher PDFPeer reviewe

Report of the panel on geopotential fields: Magnetic field, section 9

The objective of the NASA Geodynamics program for magnetic field measurements is to study the physical state, processes and evolution of the Earth and its environment via interpretation of measurements of the near Earth magnetic field in conjunction with other geophysical data. The fields measured derive from sources in the core, the lithosphere, the ionosphere, and the magnetosphere. Panel recommendations include initiation of multi-decade long continuous scalar and vector measurements of the Earth's magnetic field by launching a five year satellite mission to measure the field to about 1 nT accuracy, improvement of our resolution of the lithographic component of the field by developing a low altitude satellite mission, and support of theoretical studies and continuing analysis of data to better understand the source physics and improve the modeling capabilities for different source regions

Spitzer Observations of GX17+2: Confirmation of a Periodic Synchrotron Source

GX17+2 is a low-mass X-ray binary (LMXB) that is also a member of a small family of LMXBs known as "Z-sources" that are believed to have persistent X-ray luminosities that are very close to the Eddington limit. GX17+2 is highly variable at both radio and X-ray frequencies, a feature common to Z-sources. What sets GX17+2 apart is its dramatic variability in the near-infrared, where it changes by ΔK ~ 3 mag. Previous investigations have shown that these brightenings are periodic, recurring every 3.01 days. Given its high extinction (A_V≥9 mag), it has not been possible to ascertain the nature of these events with ground-based observations. We report mid-infrared Spitzer observations of GX17+2 which indicate a synchrotron spectrum for the infrared brightenings. In addition, GX17+2 is highly variable in the mid-infrared during these events. The combination of the large-scale outbursts, the presence of a synchrotron spectrum, and the dramatic variability in the mid-infrared suggest that the infrared brightening events are due to the periodic transit of a synchrotron jet across our line of sight. An analysis of both new, and archival, infrared observations has led us to revise the period for these events to 3.0367 days. We also present new Rossi X-Ray Timing Explorer (RXTE) data for GX17+2 obtained during two predicted infrared brightening events. Analysis of these new data, and data from the RXTE archive, indicates that there is no correlation between the X-ray behavior of this source and the observed infrared brightenings. We examine various scenarios that might produce periodic jet emission

Absence of p53 in Clara cells favours multinucleation and loss of cell cycle arrest

BACKGROUND: The p53 oncosuppressor protein is a critical mediator of the response to injury in mammalian cells and is mutationally inactivated in the majority of lung malignancies. In this analysis, the effects of p53-deficiency were investigated in short-term primary cultures of murine bronchiolar Clara cells. Clara cells, isolated from gene-targeted p53-deficient mice, were compared to cells derived from wild type littermates. RESULTS: p53 null cultures displayed abnormal morphology; specifically, a high incidence of multinucleation, which increased with time in culture. Multinucleated cells were proficient in S phase DNA synthesis, as determined by BrdU incorporation. However, multinucleation did not reflect altered rates of S phase synthesis, which were similar between wild type and p53-/- cultures. Nucleation defects in p53-/- Clara cells associated with increased centrosome number, as determined by confocal microscopy of pericentrin-stained cultures, and may highlight a novel role of p53 in preserving genomic integrity in lung epithelial cells. Effects of p53-deficiency were also studied following exposure to DNA damage. A p53-dependent reduction in the BrdU index was observed in Clara cells following ionizing radiation. The reduction in BrdU index in wild type cells displayed serum-dependency, and occurred only in the absence of serum. Taken together, these findings demonstrate that in murine primary Clara cell culture, cell cycle arrest is a p53-mediated response to DNA damage, and that extracellular factors, such as serum, influence this response. CONCLUSION: These findings highlight functions of wild type p53 protein in bipolar spindle formation, centrosome regulation, and growth control in bronchiolar Clara cells

Task-Related Deactivation and Functional Connectivity of the Subgenual Cingulate Cortex in Major Depressive Disorder

Background: Major depressive disorder is associated with functional alterations in activity and resting-state connectivity of the extended medial frontal network. In this study we aimed to examine how task-related medial network activity and connectivity were affected in depression. Methods: 18 patients with major depressive disorder, aged 15- to 24-years-old, were matched with 19 healthy control participants. We characterized task-related activations and deactivations while participants engaged with an executive-control task (the multi-source interference task, MSIT). We used a psycho-physiological interactions approach to examine functional connectivity changes with subgenual anterior cingulate cortex. Voxel-wise statistical maps for each analysis were compared between the patient and control groups. Results: There were no differences between groups in their behavioral performances on the MSIT task, and nor in patterns of activation and deactivation. Assessment of functional connectivity with the subgenual cingulate showed that depressed patients did not demonstrate the same reduction in functional connectivity with the ventral striatum during task performance, but that they showed greater reduction in functional connectivity with adjacent ventromedial frontal cortex. The magnitude of this latter connectivity change predicted the relative activation of task-relevant executive-control regions in depressed patients. Conclusion: The study reinforces the importance of the subgenual cingulate cortex for depression, and demonstrates how dysfunctional connectivity with ventral brain regions might influence executive–attentional processes