Necdin-related MAGE proteins differentially interact with the E2F1 transcription factor and the p75 neurotrophin receptor.
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.
Kuwako
Ken-ichiro
K
Division of Regulation of Macromolecular Functions, Institute for Protein Research, Osaka University, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan.
Taniura
Hideo
H
Yoshikawa
Kazuaki
K
D000818:Animals; D000951:Antigens, Neoplasm; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D018797:Cell Cycle Proteins; D002455:Cell Division; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D051379:Mice; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D011233:Precipitin Tests; D021381:Protein Transport; D011506:Proteins / Q000737:chemistry / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000502:physiology*; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins
D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D014157:Transcription Factors; C493754:E2f1 protein, mouse; C510822:MAGEL2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins; C403091:Magel2 protein, mouse; C069766:necdin