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J. Biol. Chem., Vol. 279, Issue 3, 1703-1712, January 16, 2004

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Necdin-related MAGE Proteins Differentially Interact with the E2F1 Transcription Factor and the p75 Neurotrophin Receptor^*

Ken-ichiro Kuwako, Hideo Taniura, and Kazuaki Yoshikawa

From the Division of Regulation of Macromolecular Functions, Institute for Protein Research, Osaka University, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan

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.

Received for publication, August 1, 2003 , and in revised form, October 29, 2003.

^* This work was supported in part by a grant-in-aid for the National Project on Protein Structure and Functional Analysis from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Laboratory of Molecular Pharmacology, Graduate School of Natural Science and Technology, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934, Japan.

To whom correspondence should be addressed: Division of Regulation of Macromolecular Functions, Institute for Protein Research, Osaka University, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan. Fax: 81-66879-8623; E-mail: yoshikaw{at}protein.osaka-u.ac.jp.

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