A cDNA encoding a novel protein was cloned from ischemic rat brain and found to be homologous to testis Mea-2 Golgi-associated protein (Golga3). The sequence predicted a 165-kDa protein, and in vitro translated protein exhibited a molecular mass of 165-170 kDa. Because brain ischemia induced the mRNA, and the protein localized to the Golgi apparatus, this protein was designated Ischemia-Inducible Golgin Protein 165 (IIGP165). In HeLa cells, serum and glucose deprivation-induced caspase-dependent cleavage of the IIGP165 protein, after which the IIGP165 fragments translocated to the nucleus. The C-terminus of IIGP165, which contains a LXXLL motif, appears to function as a transcriptional co-regulator. Akt co-localizes with IIGP165 protein in the Golgi in vivo, and phosphorylates IIGP165 on serine residues 345 and 134. Though transfection of IIGP165 cDNA alone does not protect HeLa cells from serum deprivation or Brefeldin-A-triggered cell death, co-transfection of both Akt and IIGP165 cDNA or combined IIGP165-transfection with PDGF treatment significantly protects HeLa cells better than either treatment alone. These data show that Akt phosphorylation of IIGP165 protects against apoptotic cell death, and add to evidence that the Golgi apparatus also plays a role in regulating apoptosis.