During the proposed renewal period, we will extend advances made in the preceding five years. These involve a number of areas. Proposals described in detail in the Research Design section include elucidating further our discovery that IP7 physiologically phosphorylates a variety of proteins in diverse species. We will also continue our studies establishing IP6 kinase-2 as a physiologic mediator of cell death. We will clarify our observations that the enzyme we first discovered as inositol polyphosphate multikinase (IPMK) also is a major nuclear PI3-kinase. Additionally, we will move forward working out a novel cell death cascade whereby apoptotic stimuli activate inducible NO synthase to generate NO that S-nitrosylates glyceraldehyde- 3-phosphate dehydrogenase (GAPDH) enabling it to bind Siah, translocate to the nucleus and cause cell death by enhancing the turnover of as yet unspecified proteins.