The evolutionarily conserved p53 protein and its cellular pathways mediate tumour suppression through an informed, regulated and integrated set of responses to environmental perturbations resulting ...in either cellular death or the maintenance of cellular homeostasis. The p53 and MDM2 proteins form a central hub in this pathway that receives stressful inputs via MDM2 and respond via p53 by informing and altering a great many other pathways and functions in the cell. The MDM2-p53 hub is one of the hubs most highly connected to other signalling pathways in the cell, and this may be why TP53 is the most commonly mutated gene in human cancers. Initial or truncal TP53 gene mutations (the first mutations in a stem cell) are selected for early in cancer development inectodermal and mesodermal-derived tissue-specific stem and progenitor cells and then, following additional mutations, produce tumours from those tissue types. In endodermal-derived tissue-specific stem or progenitor cells, TP53 mutations are functionally selected as late mutations transitioning the mutated cell into a malignant tumour. The order in which oncogenes or tumour suppressor genes are functionally selected for in a stem cell impacts the timing and development of a tumour.
•Many studies on plant nitrogen report only the total amounts of the element.•Nitrate is a major nitrogen source for higher plants.•Elevated CO2 inhibits nitrate assimilation in the shoots of C3 ...plants.•Protein concentrations decline at elevated CO2 in plants reliant on nitrate.•Plant productivity will increasingly depend on the balance among nitrogen sources.
Many studies of plant nitrogen relations assess only the total amount of the element available from the soil and the total amount of the element within the plant. Nitrogen, however, is a constituent of diverse compounds that participate in some of the most energy-intensive reactions in the biosphere. The following characterizes some of these reactions, especially those that involve ammonium and nitrate, and highlights the importance of distinguishing both among the nitrogen sources available to plants and among the nitrogen forms within plants when considering plant responses to rising atmospheric CO2 concentrations.
The
field was born from a marriage of the techniques of cancer virus research and immunology. Over the past 40 years, it has followed the path of cancer research. Now cancer treatments are turning to ...immunotherapy, and there are many hints of the role of the p53 protein in both the regulation of the innate immune system and as an antigen in adaptive immune responses. The
gene and protein are part of the innate immune system, and play an important role in infectious diseases, senescence, aging, and the surveillance of repetitive DNA and RNAs. The mutant form of the p53 protein in cancers elicits both a B-cell antibody response (a tumor antigen) and a CD-8 killer T-cell response (a tumor-specific transplantation antigen). The future will take the
-immune response field of research into cancer immunotherapy, autoimmunity, inflammatory responses, neuro-degeneration, aging, and life span, and the regulation of epigenetic stability and tissue regeneration. The next 40 years will bring the
gene and its proteins out of a cancer focus and into an organismic and environmental focus.
C₃carbon fixation has a bad reputation, primarily because it is associated with photorespiration, a biochemical pathway thought to waste a substantial amount of the carbohydrate produced in a plant. ...This review presents evidence collected over nearly a century that (1) Rubisco when associated with Mn²⁺generates additional reductant during photorespiration, (2) this reductant participates in the assimilation of nitrate into protein, and (3) this nitrate assimilation facilitates the use of a nitrogen source that other organisms tend to avoid. This phenomenon explains the continued dominance of C₃plants during the past 23 million years of low CO₂atmospheres as well as the decline in plant protein concentrations as atmospheric CO₂rises.
Thirty years ago p53 was discovered as a cellular partner of simian virus 40 large T-antigen, the oncoprotein of this tumour virus. The first decade of p53 research saw the cloning of p53 DNA and the ...realization that p53 is not an oncogene but a tumour suppressor that is very frequently mutated in human cancer. In the second decade of research, the function of p53 was uncovered: it is a transcription factor induced by stress, which can promote cell cycle arrest, apoptosis and senescence. In the third decade after its discovery new functions of this protein were revealed, including the regulation of metabolic pathways and cytokines that are required for embryo implantation. The fourth decade of research may see new p53-based drugs to treat cancer. What is next is anybody's guess.
The p53 protein is a transcription factor that prevents tumors from developing. In spontaneous and inherited cancers there are many different missense mutations in the DNA binding domain of the TP53 ...gene that contributes to tumor formation. These mutations produce a wide distribution in the transcriptional capabilities of the mutant p53 proteins with over four logs differences in the efficiencies of forming cancers in many diverse tissue types. These inherited and spontaneous TP53 mutations produce proteins that interact with both genetic and epigenetic cellular modifiers of p53 function and their inherited polymorphisms to produce a large number of diverse phenotypes in individual patients. This manuscript reviews these variables and discusses how the combinations of TP53 genetic alterations interact with genetic polymorphisms, epigenetic alterations, and environmental factors to begin predicting and modifying patient outcomes and provide a better understanding for new therapeutic opportunities.
It is only recently that drugs targeting K-RAS and Tp53 missense mutations have been developed, and along with the allele specific nature of some of these drugs comes the possibility of combining ...them with the immunologic therapies for cancers. It has taken about 40 years since their discoveries to understand the pathways they command, how they function, and how they interact with the environment of the cells they control. This communication focuses on the transfer of some of the hard won information about the p53 protein, its mutations, structures, and activities learned in the basic science laboratory and translated to the clinic.
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