A similar limitation is encountered by the PANTHER database

out accumulating new mutations. Also, while hypoxic conditions might favor a glycolytic activation in general, hypoxia is not an essential component for a tumor to become glycolytic, as in this system, where Hif is stabilized by alternative means in a normoxic environment. Pvract triggers two parallel pathways in a Ras dependent manner. The first is the PI3K/Akt pathway that targets the S6K protein important for translational initiation. The second is the Raf/ERK Wang et al. eLife 2016;5:e18126. DOI: 10.7554/eLife.18126 11 of 21 Research article Cell Biology Developmental Biology and Stem Cells Wang et al. eLife 2016;5:e18126. DOI: 10.7554/eLife.18126 12 of 21 Research article Cell Biology Developmental Biology and Stem Cells pathway targeting the L6K protein that is also independently required for translational initiation. On their own, any one of these pathways can cause tumor growth, presumably due to independent downstream transcriptional events. But both pathways must act simultaneously in order to establish translational control of both Hifa, and PDHK. Interestingly, while the PI3K and ERK pathways acting together causes significant amounts of PDHK translation, the protein thus produced is inactive. In contrast, the PDHK translated in a Pvract background is enzymatically active and capable of inactivating PDH. Our data show that yet another parallel pathway initiated by Pvract that involves Src and JNK helps generate the active form of PDHK. Therefore all three downstream effectors of activated Pvr are essential in generating an active form of PDHK protein to down-regulate oxidative phosphorylation, while only the last two of these pathways are needed for LDH production and glycolysis. It is easy to visualize how, in the context of the triggering oncogene, the tumor caused could either be non-glycolytic, or be glycolytic Wang et al. eLife 2016;5:e18126. DOI: 10.7554/eLife.18126 13 of 21 Research article Cell Biology Developmental Biology and Stem Cells but not lacking in oxidative phosphorylation. In the system described in this paper, it is Inevitable that direct pyruvate to acetyl-CoA conversion within the mitochondrion, and therefore the TCA flux will be attenuated since PDH function is inhibited by PDHK in the tumor cells. However, we do not have direct evidence for or against any bypass mechanisms such as those using glutamine as the primary driver of anabolic processes being operational in the context of the Drosophila Pvract induced tumors as they are for many cancers. This issue requires further direct measurement of metabolic activity of the tumor tissue in the near future. While this sequence of events can initiate a switch in the metabolic profile of the cell, an additional mechanism is required to sustain this transition over a long period of time. The central player in this sustenance is ROS. The level of these CF-101 site free-radical species rises as the mitochondrion becomes dysfunctional. Importantly, this excess ROS functions as a feedback signal PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19825521 that has at least two important consequences. First, ROS stabilizes Hif using the same mechanism that is used during hypoxia, thus reinforcing the glycolytic pathways. The second is that ROS can activate the JNK pathway. Thus, after the initial reprogramming in metabolism, the transition is made stable over time, as the generated ROS reinforces the upstream members. All of the results shown here are consistent with this positive feedback model that enforces the Warburg effect and su