FOXO proteins are transcriptional regulators that control cell cycle progression, DNA repair, defense against oxidative damage and apoptosis. These divergent functions of FOXO proteins are regulated by signal-induced, post-translational modifications. Phosphorylation of cytoplasmic FOXO at specific sites by JNK initiates translocation into the nucleus. Acetylation and deacetylation of nuclear FOXO affects the selection of transcriptional programs that are controlled by FOXO proteins. Activation of Akt by growth factors results in phosphorylation of nuclear FOXO at specific sites followed by additional phosphorylations mediated by other kinases. Akt-dependent phosphorylation reduces the DNA-binding activity of FOXO, interferes with binding to the co-activators p300/CBP, and inactivates the FOXO nuclear translocation signal. The Akt-phosphorylated FOXO is exported from the nucleus in a CRM1- and 14-3-3-dependent process. Cytoplasmic, Akt-phosphorylated FOXO interacts with the ubiquitin ligase Skp2 and is targeted for proteasomal degradation. The nuclear-cytoplasmic "FOXO shuttle" is driven by stress signals that result in nuclear import and FOXO transcriptional activity and growth signals that initiate nuclear export and proteasomal degradation of FOXO.

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The large RNase T,-resistant oligonucleotides of the nondefective (nd) Rous sarcoma viruses (RSV): Prague RSV of subgroup B (PR-B), PR-C and B77 of subgroup C; of their transformation-defective (td) deletion mutants: td PR-B, td PR-C, and td B77; and of replication-defective (rd) RSV(-) were completely or partially mapped on the 30 to 40S viral RNAs. The location of a given oligonucleotide relative to the poly(A) terminus of the viral RNAs was directly deduced from the smallest size of the poly(A)-tagged RNA fragment from which it could be isolated. Identification of distinct oligonucleotides was based on their

Akt (cellular homolog of murine thymoma virus akt8 oncogene) is an essential component of the PI3K (phosphatidylinositol 3-kinase) pathway. Its activity is stimulated by receptor tyrosine kinases and G-protein coupled receptors and plays a critical role in the regulation of cell proliferation, differentiation and apoptosis. A gain of function in Akt can lead to uncontrolled cell proliferation and resistance to apoptosis, both hallmarks of oncogenic transformation. In this communication, we have investigated the phosphorylation at the Akt residues T308, S473 and T450 and their roles in oncogenic transformation and signaling. We find that T450 phosphorylation has only a minimal part in these activities. In contrast, the phosphorylation of T308 and of S473 fulfills essential, distinct, and non-overlapping functions that we define with inactivating and with phosphomimetic mutations of these sites.