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J. Biol. Chem., Vol. 282, Issue 8, 5736-5748, February 23, 2007

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-Synuclein Stimulates Differentiation of Osteosarcoma Cells

RELEVANCE TO DOWN-REGULATION OF PROTEASOME ACTIVITY^*

Masayo Fujita, Shuei Sugama, Masaaki Nakai, Takato Takenouchi, Jianshe Wei, Tomohiko Urano^¶, Satoshi Inoue^¶, and Makoto Hashimoto¹

From the Laboratory for Chemistry and Metabolism, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan, Transgenic Animal Research Center, National Institute of Agrobiological Sciences, Tsukuba, Ibaraki 305-8634, Japan, and ^¶Department of Geriatrics and Gerontology, School of Medicine, University of Tokyo, Tokyo 113-8655, Japan

Because a limited study previously showed that -synuclein (-syn), the major pathogenic protein for Parkinson disease, was expressed in differentiating brain tumors as well as various peripheral cancers, the main objective of the present study was to determine whether -syn might be involved in the regulation of tumor differentiation. For this purpose, -syn and its non-amyloidogenic homologue -syn were stably transfected to human osteosarcoma MG63 cell line. Compared with -syn-overexpressing and vector-transfected cells, -syn-overexpressing cells exhibited distinct features of differentiated osteoblastic phenotype, as shown by up-regulation of alkaline phosphatase and osteocalcin as well as inductive matrix mineralization. Further studies revealed that proteasome activity was significantly decreased in -syn-overexpressing cells compared with other cell types, consistent with the fact that proteasome inhibitors stimulate differentiation of various osteoblastic cells. In -syn-overexpressing cells, protein kinase C (PKC) activity was significantly decreased, and reactivation of PKC by phorbol ester significantly restored the proteasome activity and abrogated cellular differentiation. Moreover, activity of lysosome was up-regulated in -syn-overexpressing cells, and treatment of these cells with autophagy-lysosomal inhibitors resulted in a decrease of proteasome activity associated with up-regulation of -syn expression, leading to enhance cellular differentiation. Taken together, these results suggest that the stimulatory effect of -syn on tumor differentiation may be attributed to down-regulation of proteasome, which is further modulated by alterations of various factors, such as protein kinase C signaling pathway and a autophagy-lysosomal degradation system. Thus, the mechanism of -syn regulation of tumor differentiation and neuropathological effects of -syn may considerably overlap with each other.

Received for publication, June 28, 2006 , and in revised form, December 15, 2006.

^* This work was supported in part by a grant-in-aid for Science Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan and a project grant from Tokyo Metropolitan Organization. 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.

¹ To whom correspondence should be addressed: Laboratory for Chemistry and Metabolism, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526, Japan. Tel.: 81-42-325-3881; Fax: 81-42-321-8678; E-mail address: mhashimoto{at}tmin.ac.jp.

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