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標題: 探討Cdk5蛋白對於乳癌細胞生物功能的調控
Investigation of Biological Functions of Cdk5 in Breast Cancer Cells
作者: 林赫
關鍵字: 基礎醫學類;基礎研究
Cdk5(cyclin-dependent kinase 5)的特色為其活化蛋白並非cyclin而主要是p35,早期的研究著重在神經系統方面並於神經退化性疾病中扮演重要角色。主持人已發表的論文指出Cdk5經由專一機制調控甲狀腺癌及攝護腺癌細胞增生。至於乳癌方面,主持人的初步結果指出Cdk5/p35蛋白表現量與乳癌細胞生長有正相關(詳見初步結果三),且來自彰濱秀傳醫院合作計畫的臨床檢體證實,Cdk5/p35蛋白量在腫瘤組織明顯比鄰近正常組織高(詳見初步結果一及二)。基於上述線索,本計畫旨在探討Cdk5/p35蛋白對於乳癌細胞之生物功能的調控及其上下游訊息傳遞機制。計畫內容重點為:1. 觀察不同的Cdk5/p35蛋白表現量或活性(包括突變)對於乳癌細胞之各項生物功能影響(包括增生、細胞週期、凋亡、附著、移動、侵入);2. 評估EGFR、Her2、c-Abl等tyrosine kinase是否為Cdk5/p35蛋白及活性的上游調控因子;3. 評估ERα、p53、p21WAF/Cip1、STAT3、TC10α、c-cbl是否為Cdk5/p35直接或間接的下游訊息傳遞蛋白(包括觀察各因子之轉錄活性、蛋白穩定度、核質分佈、影響細胞骨架組成);4. 利用人類腫瘤細胞異種移植模式(於裸鼠)驗證上述於細胞株中的發現;5. 利用購得的乳癌病患切片(商品不須人體試驗證明)驗證Cdk5/p35表現是否與上述研究之上下游因子表現具有相關性。經由以上研究設計期望能從基礎研究角度充分了解Cdk5/p35對於乳癌的重要性,並對於未來診斷及治療有所貢獻。

Cdk5 (cyclin-dependent kinase 5) belongs to CDK family. However, the activator of Cdk5 is not cyclin, but p35. The investigation of Cdk5 was primarily focused on the roles in central nervous system including neurodegenerative diseases. Principle investigator's published results indicate that Cdk5 can regulate proliferation of both thyroid cancer cells and prostate cancer cells through specific mechanisms. As regards to breast cancer, principle investigator's preliminary results showed the positive correlation between Cdk5/p35 levels and breast cancer cell proliferation (see the preliminary data 3). Clinical data also confirmed that protein levels of Cdk5/p35 in tumor tissues were higher than those in normal ones (patients' specimen was provided from Chang Bing Show Chwan Memorial Hospital due to collaboration) (see the preliminary data 1 and 2). Therefore, the goal of this grant is to investigate the roles and mechanisms of Cdk5/p35 which regulate the biological functions of breast cancer cells. The strategies are: 1. Investigate the effects of different Cdk5/p35 levels or activity (includes mutants) on biological functions of breast cancer cells (includes proliferation, cell cycle, apoptosis, adhesion, migration, and invasion). 2. Evaluate whether tyrosine kinases, such as EGFR, Her2, and c-Abl, as upstream factors, can directly or indirectly regulate Cdk5/p35 protein expression or activity. 3. Evaluate whether ERα, p53, p21WAP/Cip1, STAT3, TC10α, c-cbl can be directly or indirectly regulated by Cdk5/p35 as downstream factors (observe transcriptional activity, protein stability, subcellular localization, cytoskeletal change). 4. Take advantage of nude mice xenograft model to testify the hypothetical findings from breast cancer cell lines. 5. Using the commercial tissue array chips of breast cancer (IRB unnecessary) to testify the hypothetical correlation among Cdk5/p35 and those proteins described above. Base on these experimental designs, principle investigator expects to understand the roles of Cdk5/p35 in breast cancer from the view points of basic research and hope these outcomes in the future can contribute to the diagnosis and treatment of breast cancer.
其他識別: NSC100-2320-B005-002
Appears in Collections:生命科學系所

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