resence of lactate dehydrogenase, pyruvate is converted to lactate. In contrast, oxidative phosphorylation requires the mitochondrial enzyme complex pyruvate dehydrogenase that converts pyruvate to acetylCoA, essential for the initiation of the tricarboxylic acid cycle. PDH is rendered inactive when it is phosphorylated by pyruvate dehydrogenase kinase and is activated when dephosphorylated by the phosphatase, PDHP. Many cancers maintain high ox-phos as well as glycolysis, maximizing the anapleuretic functions of the cell that provide the building blocks for lipid, protein and nucleotide synthesis. The mammalian transcription factor, Hypoxia-inducible factor-1a, regulates a number of target genes that promote various aspects of cancer, including metabolism, angiogenesis, cell survival, drug resistance, and invasive motility. Hif-1a participates in this process as hypoxia favors glycolysis over oxidative phosphorylation for ATP generation. Hypoxia has been the proposed mechanism for oncogenes to effect a change in metabolic state. Mammalian studies often involve immortalized cell-lines with a variable and often unknown genetic background. LBH589 web Furthermore, while initiation of glycolysis has been studied, the mechanism for the maintenance of the altered metabolic state under normoxic conditions is not as clear. Using Drosophila as a model system, we provide here, a complete genetic dissection of one mechanism that leads to and sustains a metabolic reprogramming in which Hifa, but not hypoxia, plays an important role. Hif-1a and c-Jun N-terminal kinase are associated together in many tumor types. It is well established that reactive oxygen species such as superoxide and peroxide radicals can cause both activation of the JNK pathway and stabilization of Hif-1a . It is increasingly apparent that persistent activation of JNK signaling is 
involved in cancer development, progression and perhaps cellular transformation. In addition to the above functions, it is likely that JNK could have an indirect role in attenuating oxidative phosphorylation by activating PDHK, thus blocking PDH function. Determining how a variety of oncogenic pathways interact together to cause the metabolic reprogramming from oxidative phosphorylation to glycolysis is the central focus of this investigation. We achieve this by activating a single oncogene and show that this leads to a cascade of events that ultimately cause a glycolytic activation and allow maintenance of this altered metabolic state. There are multiple ways to model the ‘Warburg effect’. This study takes advantage of the powerful genetic techniques in Drosophila used to identify epistatic relationships to provide a comprehensive and mechanistic basis for the establishment and maintenance of this metabolic transition in a receptor PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19825579 tyrosine kinase induced tumor. Results LDH activation and transcription by a specific RTK Aerobic glycolysis in tumors is characterized by the conversion of pyruvate to lactate by the enzyme, lactate dehydrogenase. Importantly, LDH has been demonstrated to be a marker for poor prognosis in multiple malignancies such as renal cell carcinoma. The Drosophila genome contains a single gene encoding an LDH enzyme, and biochemical studies demonstrate that it functions most like LDHA, the human form predominantly expressed in skeletal muscle that favors the conversion of pyruvate to lactate. An increase in LDHA enzymatic activity has been observed in diverse malignant cancers. Wang et al. eLif