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下記のように臨床研セミナーを開催します。
事前連絡なしにご自由にご参加ください。なお臨床研は、上北沢に引っ越し、最寄りは京
王線上北沢駅あるいは八幡山駅です。
http://www.rinshoken.or.jp/access/index.html
をご参照ください。お間違えのないように。

日時:平成22年10月25日(月)14:30-15:30
場所:東京都臨床医学総合研究所(世田谷区上北沢2-1-6)、二階講堂
演者:Slavica TUDZAROVA-TRAJKOVSKA博士 (Wolfson Institute for Biomedical Research&s_comma;
University College London&s_comma; UK)
演題:MOLECULAR ARCHITECTURE OF THE DNA REPLICATION ORIGIN ACTIVATION CHECKPOINT
(和訳 動物細胞DNA複製活性化チェックポイントの分子メカニズム)

要旨
Perturbation of the DNA replication initiation pathway arrests human somatic cells
in G1&s_comma; pointing towards a cell cycle checkpoint for replication-competent origins.
We used RNAi against Cdc7 kinase to block replication initiation and dissect the
molecular nature of this checkpoint in primary fibroblasts. Our results show that the
checkpoint response is dependent on three axes coordinated through the Forkhead
transcription factor FoxO3a. In G1 arrested cells&s_comma; FoxO3a activates the ARF
┤Mdm2┤p53→p21 pathway and mediates upregulation of p15 and p27. p53 in turn
activates expression of the Wnt/b-catenin signaling antagonist Dickkopf 3 (Dkk3)&s_comma;
leading to Myc and cyclin D1 downregulation. Gene expression microarrays show the
resulting loss of CDK activity inactivates the Rb-E2F pathway&s_comma; overriding the regular
G1-S transcriptional program. Primary fibroblasts concomitantly depleted of
Cdc7/FoxO3a&s_comma; Cdc7/p15&s_comma; Cdc7/p53 or Cdc7/Dkk3 are all able to bypass the cell cycle blockade
a!
nd proceed into an abortive S phase followed by apoptosis. Our findings explain
how somatic cells delay S phase entry until a threshold of replication-competent
origins is reached to ensure complete genome duplication. The lack of redundancy
between the checkpoint axes and reliance on several tumour suppressor proteins commonly
inactivated in human tumors provides a mechanistic basis for the
cancer-cell-specific killing observed with Cdc7 small molecule inhibitors.

[世話人:正井久雄(ゲノム動態プロジェクト)]

Hisao Masai
Genome Dynamics Project&s_comma;
Tokyo Metropolitan Institute of Medical Science&s_comma;
2-1-6 Kamikitazawa&s_comma; Setagaya-ku&s_comma; Tokyo 156-8506&s_comma; JAPAN
Tel: 81-3-5316-3231 Fax: 81-3-5316-3145; E-mail: masai-hs@igakuken.or.jp
http://www.rinshoken.or.jp/CB/index-jp.htm

正井 久雄
東京都臨床医学総合研究所 ゲノム動態プロジェクト
郵便番号 156-8506
所在地  東京都世田谷区上北沢二丁目1番6号
正井直通電話 03-5316-3231
研究室電話 03-5316-3117
研究室FAX 03-5316-3145
E-mail masai-hs@igakuken.or.jp



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