The In Vivo Role of the RP-Mdm2-p53 Pathway in Signaling Oncogenic Stress Induced by pRb Inactivation and Ras Overexpression

The Mdm2-p53 tumor suppression pathway plays a vital role in regulating cellular homeostasis by integrating a variety of stressors and eliciting effects on cell growth and proliferation. Recent studies have demonstrated an in vivo signaling pathway mediated by ribosomal protein (RP)-Mdm2 interaction that responds to ribosome biogenesis stress and evokes a protective p53 reaction. It has been shown that mice harboring a Cys-to-Phe mutation in the zinc finger of Mdm2 that specifically disrupts RP L11-Mdm2 binding are prone to accelerated lymphomagenesis in an oncogenic c-Myc driven mouse model of Burkitt's lymphoma. Because most oncogenes when upregulated simultaneously promote both cellular growth and proliferation, it therefore stands to reason that the RP-Mdm2-p53 pathway might also be essential in response to oncogenes other than c-Myc. Using genetically engineered mice, we now show that disruption of the RP-Mdm2-p53 pathway by an Mdm2C305F mutation does not accelerate prostatic tumorigenesis induced by inactivation of the pRb family proteins (pRb/p107/p130). In contrast, loss of p19Arf greatly accelerates the progression of prostate cancer induced by inhibition of pRb family proteins. Moreover, using ectopically expressed oncogenic H-Ras we demonstrate that p53 response remains intact in the Mdm2C305F mutant MEF cells. Thus, unlike the p19Arf-Mdm2-p53 pathway, which is considered a general oncogenic response pathway, the RP-Mdm2-p53 pathway appears to specifically suppress tumorigenesis induced by oncogenic c-Myc

Equilibrium configurations of two charged masses in General Relativity

An asymptotically flat static solution of Einstein-Maxwell equations which describes the field of two non-extreme Reissner - Nordstr\"om sources in equilibrium is presented. It is expressed in terms of physical parameters of the sources (their masses, charges and separating distance). Very simple analytical forms were found for the solution as well as for the equilibrium condition which guarantees the absence of any struts on the symmetry axis. This condition shows that the equilibrium is not possible for two black holes or for two naked singularities. However, in the case when one of the sources is a black hole and another one is a naked singularity, the equilibrium is possible at some distance separating the sources. It is interesting that for appropriately chosen parameters even a Schwarzschild black hole together with a naked singularity can be "suspended" freely in the superposition of their fields.Comment: 4 pages; accepted for publication in Phys. Rev.

Enzyme sequestration as a tuning point in controlling response dynamics of signalling networks

Signalling networks result from combinatorial interactions among many enzymes and scaffolding proteins. These complex systems generate response dynamics that are often essential for correct decision-making in cells. Uncovering biochemical design principles that underpin such response dynamics is a prerequisite to understand evolved signalling networks and to design synthetic ones. Here, we use in silico evolution to explore the possible biochemical design space for signalling networks displaying ultrasensitive and adaptive response dynamics. By running evolutionary simulations mimicking different biochemical scenarios, we find that enzyme sequestration emerges as a key mechanism for enabling such dynamics. Inspired by these findings, and to test the role of sequestration, we design a generic, minimalist model of a signalling cycle, featuring two enzymes and a single scaffolding protein. We show that this simple system is capable of displaying both ultrasensitive and adaptive response dynamics. Furthermore, we find that tuning the concentration or kinetics of the sequestering protein can shift system dynamics between these two response types. These empirical results suggest that enzyme sequestration through scaffolding proteins is exploited by evolution to generate diverse response dynamics in signalling networks and could provide an engineering point in synthetic biology applications

Leadership after virtue: MacIntyre’s critique of management reconsidered

MacIntyre argues that management embodies emotivism, and thus is inherently amoral and manipulative. His claim that management is necessarily Weberian is, at best, outdated, and the notion that management aims to be neutral and value free is incorrect. However, new forms of management, and in particular the increased emphasis on leadership which emerged after MacIntyre’s critique was published, tend to support his central charge. Indeed, charismatic and transformational forms of leadership seem to embody emotivism to a greater degree than do more Weberian, bureaucratic forms of management, so MacIntyre’s central contention about our emotivistic culture seems to be well-founded. Having criticised the details but defended the essence of MacIntyre’s critique of management, this paper sketches a MacIntyrean approach to management and leadership by highlighting the affinities between MacIntyre’s political philosophy and Greenleaf’s concept of servant leadership

A new experimental rat model of osteosarcoma established by intrafemoral tumor cell inoculation, useful for biology and therapy investigations

Satisfactory experimental models for preclinical cancer studies must follow several criteria: (1) reproducibility of the method used to induce the tumor and (2) clinical, pathological and kinetic similarity with the corresponding human tumors. We developed a model of osteosarcoma locally induced by the intrafemoral injection of osteosarcoma (OSR) cells in Sprague-Dawley rats. This method yields nearly 80% of bone tumors at the injection site. These tumors double their volume fairly slowly (in approximately 20 days) and lung metastases occur in 96% of the animals. The OSR cell-induced tumor is characterized by a direct production of mineralized matrix by the tumor cells themselves, as revealed by histochemical analysis. The microarchitectural parameters which were quantified by a microscanner show an increased trabecular bone volume (+238%) when OSR cells were injected in the femur, as compared to controls injected with vehicle. Osteoblastic markers such as alkaline phosphatase, osteopontin, osteocalcin and bone sialoprotein were expressed by the tumor in vivo, whereas the initially injected OSR cells did not express some of these markers, suggesting that OSR cells reacquired an osteoblastic phenotype in a favorable environment. The clinical, radiological and histological data show that this model shares high similarities with the osteocondensing forms of osteosarcoma in humans