We have recently identified Np9 as a novel nuclear protein produced by the human endogenous retrovirus K and were able to document the exclusive presence of np9 transcript in tumors and transformed cells. With the aim of studying whether Np9 has a role in tumorigenesis, a systematic search for interacting proteins was performed. Here, we identify the RING-type E3 ubiquitin ligase LNX (ligand of Numb protein X) as an Np9-interacting partner. We furthermore show that the interaction involves N-and C-terminal domains of both proteins and can affect the subcellular localization of LNX. LNX has been reported to target the cell fate determinant and Notch antagonist Numb for proteasome-dependent degradation, thereby causing an increase in transactivational activity of Notch. We document that LNX-interacting Np9, like Numb, is unstable and degraded via the proteasome pathway and that ectopic Numb can stabilize recombinant Np9. Combined, these findings point to the possibility that Np9 affects tumorigenesis through the LNX/Numb/Notch pathway.Up to 8% of the human genome consists of retrovirusderived sequences (19). They are the result of numerous infections and subsequent integration of proviral elements into the germ line of human ancestors during the past 40 million years (2). Most of the recent human endogenous retrovirus (HERV) elements are defective due to the accumulation of mutations. Nonetheless, retroviral genes are frequently expressed in normal and transformed human tissues. The function of these genes in normal human cell physiology is still unclear (32). So far, only the expression of the env gene of HERV-W is known to have a crucial function in normal organismal physiology, namely human trophoblast cell fusion and differentiation (5,12,23). In contrast, retroviral gene expression has been linked to several human diseases, including tumorigenesis. In particular, expression of HERV-K seems to be strongly associated with transformation. Early hints pointing in this direction came from the observation that expression of the HERV-K proteins Gag and Env, as well as antibodies directed against these proteins, could be specifically detected in patients suffering from germ cell tumors (17,24,30,31). Other studies implicate a contribution of HERV-K10 gag RNA expression to the development of leukemia (9) or show that env as well as the expression of subgenomic env transcripts correlates with human breast cancer (35,36).It is unclear, at the present, how these proteins may support tumorigenesis. The Rev-like regulatory protein Rec (20,21)

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