"Cancer is one of the leading causes of death in Europe and one of the highlighted issues in the 7th Framework Programme. Understanding the molecular mechanisms of cancer is expected to contribute to the development of better therapeutic approaches. In this project, the applicant proposes to examine the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) and its product, fructose-2,6-bisphosphate (F2,6BP), in the regulation of the cell cycle and tumorigenesis. Increased glycolysis is a key metabolic phenotype of cancer. Oncogenic stimuli increase F2,6BP, an activator of the first irreversible step of glycolysis. Previous studies have suggested PFKFB3 to be the dominant source of F2,6BP and the culprit behind the high glycolytic activity in tumors. The applicant has recently demonstrated that PFKFB3 localizes to the nucleus, where PFKFB3-mediated synthesis of F2,6BP stimulates cells to proliferate without a significant effect on glycolysis. He then discovered that F2,6BP in the nucleus activates cyclin-dependent kinases, decreases the expression of the cell cycle suppressor p27, and increases the expression of cyclin D3. These and other previous results obtained by the applicant suggest that tumor cells may need PFKFB3 and F2,6BP in the nucleus in order to couple glucose uptake with cell division activity in the nucleus. The objectives of the project are as follows: 1-To ascertain the role of PFKFB3 in the regulation of the cell cycle and cell cycle proteins; 2-To determine if there is a genetic/functional interaction between PFKFB3 and cyclin D3, and 3-To determine the in vivo interaction of PFKFB3 and p27, and whether PFKFB3 is required for tumor susceptibility induced by p27 deficiency. This project is expected to help the applicant continue his career in his host institution where he can apply the state-of-art techniques he has learned in the USA to contribute to the European Research Area in the field of cancer research."