Journal Article

p53 activity is selectively licensed in the Drosophila stem cell compartment

Wylie, Annika, D’Brot, Alejandro, Buszczak, Michael, Lu, Wan-Jin, Abrams, John M

2014

Overview

Oncogenic stress provokes tumor suppression by p53 but the extent to which this regulatory axis is conserved remains unknown. Using a biosensor to visualize p53 action, we find that Drosophila p53 is selectively active in gonadal stem cells after exposure to stressors that destabilize the genome. Similar p53 activity occurred in hyperplastic growths that were triggered either by the RasV12 oncoprotein or by failed differentiation programs. In a model of transient sterility, p53 was required for the recovery of fertility after stress, and entry into the cell cycle was delayed in p53- stem cells. Together, these observations establish that the stem cell compartment of the Drosophila germline is selectively licensed for stress-induced activation of the p53 regulatory network. Furthermore, the findings uncover ancestral links between p53 and aberrant proliferation that are independent of DNA breaks and predate evolution of the ARF/Mdm2 axis. The most common genetic change seen in cancer patients produces a faulty version of the p53 protein, which normally restricts tissue growth. This change promotes cancer because cells can now divide faster and fail to die when they should. Much remains to be learned about how p53 functions to restrain growth. As p53 is found in primitive organisms, and cancer is unlikely to have significantly influenced evolution, suppressing tumor formation was almost certainly not the original function of this gene. Furthermore, p53 works in a different way compared to many other tumour suppressors. Therefore, prevention of cancer is likely to have evolved as a side effect derived from more ancient functions. Recently, a link between p53 and stem cells has been uncovered. Stem cells are special because they can develop into many different types of cells, and they are crucial for the growth and repair of tissues. To form a particular type of cell, the stem cell divides to create two daughter cells. Commonly, one daughter cell stays in the stem state, whereas the other becomes a particular type of cell, such as a nerve cell or muscle cell. Because of this special property, scientists hypothesize that stem cells have special mechanisms to protect them from DNA damage that might partially depend on p53. This would prevent the spread of damaged genomes that would otherwise occur among daughter cells. To learn more about how p53 influences stem cells, Wylie, Lu et al. monitored its activity in the gonads of fruit flies, which are a powerful genetic model. They found that damaging DNA activates p53 in stem cells and their daughter cells, but not in other types of cells that have been damaged. In addition, p53 is activated by the uncontrolled growth and division of stem cells in the gonad, even when DNA is not damaged. This is unexpected since molecules linking inappropriate growth to p53 were thought to be present only in mammals. Therefore, it appears that the tumor-suppressing behavior of p53 in mammals was adapted from its more ancient ability to regulate stem cell growth—an ability that evolved before organisms divided into vertebrates and invertebrates.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Binding sites / Biology / Biosensing Techniques / biosensor / Biosensors / Cell cycle / Cell Cycle Checkpoints / Cell Proliferation / Deoxyribonucleic acid / Developmental Biology and Stem Cells / DNA / DNA Damage / Drosophila / Drosophila melanogaster - genetics / Drosophila melanogaster - metabolism / Drosophila Proteins - genetics / Drosophila Proteins - metabolism / Female / Fertility / Gene expression / Gene Expression Regulation / Genomes / Genomic Instability / germline / Infertility - genetics / Infertility - metabolism / Infertility - physiopathology / Insects / Kinases / MDM2 protein / oncogenic stress / Ovary - metabolism / Ovary - pathology / Ovary - physiopathology / p53 / p53 Protein / Signal Transduction / Software / Statistical analysis / stem cell / Stem Cell Niche / Stem cells / Stem Cells - metabolism / Stem Cells - pathology / Sterility / Stress, Physiological / Time Factors / Tumor suppression / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism