Duox, Flotillin-2, and Src42A Are Required to Activate or Delimit the Spread of the Transcriptional Response to Epidermal Wounds in Drosophila

The epidermis is the largest organ of the body for most animals, and the first line of defense against invading pathogens. A breach in the epidermal cell layer triggers a variety of localized responses that in favorable circumstances result in the repair of the wound. Many cellular and genetic responses must be limited to epidermal cells that are close to wounds, but how this is regulated is still poorly understood. The order and hierarchy of epidermal wound signaling factors are also still obscure. The Drosophila embryonic epidermis provides an excellent system to study genes that regulate wound healing processes. We have developed a variety of fluorescent reporters that provide a visible readout of wound-dependent transcriptional activation near epidermal wound sites. A large screen for mutants that alter the activity of these wound reporters has identified seven new genes required to activate or delimit wound-induced transcriptional responses to a narrow zone of cells surrounding wound sites. Among the genes required to delimit the spread of wound responses are Drosophila Flotillin-2 and Src42A, both of which are transcriptionally activated around wound sites. Flotillin-2 and constitutively active Src42A are also sufficient, when overexpressed at high levels, to inhibit wound-induced transcription in epidermal cells. One gene required to activate epidermal wound reporters encodes Dual oxidase, an enzyme that produces hydrogen peroxide. We also find that four biochemical treatments (a serine protease, a Src kinase inhibitor, methyl-ß-cyclodextrin, and hydrogen peroxide) are sufficient to globally activate epidermal wound response genes in Drosophila embryos. We explore the epistatic relationships among the factors that induce or delimit the spread of epidermal wound signals. Our results define new genetic functions that interact to instruct only a limited number of cells around puncture wounds to mount a transcriptional response, mediating local repair and regeneration

Two sides of the same coin – compensatory proliferation in regeneration and cancer

Apoptosis has long been regarded as a tumor suppressor mechanism and evasion from apoptosis is considered to be one hallmark of cancer. However, this principle is not always consistent with clinical data which often illustrate a correlation between apoptosis and poor prognosis. Work in the last 15 years has provided an explanation for this apparent paradox. Apoptotic cells communicate with their environment and can produce signals which promote compensatory proliferation of surviving cells. This behavior of apoptotic cells is important for tissue regeneration in several model organisms, ranging from hydra to mammals. However, it may also play an important feature for tumorigenesis and tumor relapse. Several distinct forms of apoptosis-induced compensatory proliferation (AiP) have been identified, many of which involve reactive oxygen species (ROS) and immune cells. One type of AiP, undead AiP, in which apoptotic cells are kept in an immortalized state and continuously divide, may have particular relevance for tumorigenesis. Furthermore, given that chemo- and radiotherapy often aim to kill tumor cells, an improved understanding of the effects of apoptotic cells on the tumor and the tumor environment is of critical importance for the well-being of the patient. In this review, we summarize the current knowledge of AiP and focus our attention on recent findings obtained in Drosophila and other model organisms, and relate them to tumorigenesis