Necdin is a growth suppressor expressed predominantly in postmitotic neurons and implicated in their terminal differentiation.
Necdin shows a moderate homology to the MAGE family
proteins, the functional roles of which are largely unknown. Human genes encoding
necdin, MAGEL2 (necdin-like 1), and MAGE-G1 (necdin-like 2) are located in proximal chromosome 15q, a region associated with
neurodevelopmental disorders such as
Prader-Willi syndrome,
Angelman syndrome, and
autistic disorder. The
necdin and MAGEL2 genes are subjected to genomic imprinting and suggested to be involved in the etiology of
Prader-Willi syndrome. In this study, we compared biochemical and functional characteristics of murine orthologs of these
necdin-related MAGE
proteins. The colony formation and
bromodeoxyuridine incorporation analyses revealed that
necdin and MAGE-G1, but not MAGEL2, induced growth arrest.
Necdin and MAGE-G1 interacted with the
transcription factor E2F1 via its transactivation domain, repressed E2F1-dependent transcription, and antagonized E2F1-induced apoptosis of N1E-115
neuroblastoma cells. In addition,
necdin and MAGE-G1 interacted with the
p75 neurotrophin receptor via its distinct intracellular domains. In contrast, MAGEL2 failed to bind to these
necdin interactors, suggesting that MAGEL2 has no
necdin-like function in developing brain. Overexpression of p75 translocated
necdin and MAGE-G1 in the proximity of the plasma membrane and reduced their association with E2F1 to facilitate E2F1-induced death of
neuroblastoma cells. These results suggest that
necdin and MAGE-G1 target both E2F1 and p75 to regulate cell viability during brain development.