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標題: 探討JNK在podosome形成過程中的角色
Study on the Role of Jnk in the Formation of Podosomes
作者: 陳鴻震
關鍵字: 商品化;基礎醫學類;podosome;invadopodia;JNK;Src;組織侵犯
Podosome為細胞底部富含actin的凸出構造,與細胞外基質蛋白的分解及組織侵犯有關。此一構造最早是在致癌基因v-Src所轉型的細胞中被描述,隨後在噬骨細胞、巨噬細胞、及癌細胞中也發現有類似的構造。Podosome在Src所轉型的纖維母細胞及其他種類的細胞(如噬骨細胞)中經常被發現會彼此聚集,進而形成大而明顯的環狀構造,稱之為podosome rosettes。c-Jun N-terminal kinases (JNKs)已知與細胞增生、凋亡、移動、組織侵犯、代謝、及DNA修復有關。JNK家族有三個基因,分別是JNK1、JNK2、及JNK3。JNK1與JNK2有普遍性的表現,JNK3則侷限表現於腦、心臟、及睪丸。最近我們在初步的研究中發現:(一) JNK抑制劑SP600125會抑制v-Src轉型細胞podosome rosette的形成。(二) 利用small-hairpin RNA抑制JNK1或JNK2的表現,可部分抑制podosome rosette形成。(三) Src無法有效在NK1或JNK2基因剔除細胞中引起podosome rosette的形成。以上結果,暗示JNK可能參與podosome rosette的形成。雖然JNK已知與細胞的組織侵犯能力有關,但其在podosome rosette形成上的角色則從未被報導過。本計劃的目的在於檢驗JNK在podosome rosette形成過程中角色,並剖析其分子機轉。本計劃的達成,不僅有助於釐清JNK在podosome rosette形成過程中所扮演的角色,也有助於了解podosome rosette構造組裝的調控機轉。我們在此三年期計畫中提出以下三個研究目標:目標一、 確立JNK在podosome rosette形成過程中的角色。(第一年)目標二、探討MKK-JNK-JIP複合物的形成,在podosome rosette形成過程中的重要性。(第二年)目標三、搜尋與podosome rosette形成有關的JNK下游分子。(第三年)

Podosomes are dynamic, actin-enriched structures that represent protrusions of the ventral plasma membrane with an important role in invasive cell motility and extracellular matrix degradation. Following the discovery of podosomes in v-Src-transformed cells, similar structures were identified in osteoclasts, macrophages, and certain invasive human cancer cells. In v-Src-transformed fibroblasts and some other types of cells such as osteoclasts, podosomes are often found to assemble into large rosette-like structures. c-Jun N-terminal kinases (JNKs) has been shown to be involved in proliferation, apoptosis, motility, invasion, metabolism and DNA repair. There are three JNK genes (JNK1, JNK2, and JNK3). JNK1 and JNK2 are ubiquitously expressed, while JNK3 is restricted to brain, heart, and testis. Recently, we found (1) the JNK-specific inhibitor SP600125 suppressed the formation of podosome rosettes in Src-transformed fibroblasts, (2) depletion of JNK1 or JNK2 by small-hairpin RNA led to partial inhibition in podosome rosette formation in Src-transformed fibroblasts, and (3) oncogenic Src was deficient to induce podosome rosettes in JNK1-null cells and JNK2-null cells. These results suggest that JNK1/2 may be essential for the assembly of podosome rosettes. The goal of this proposal is to examine the role of JNK in the assembly of podosome rosettes and dissect the underlying molecular mechanisms. The achievement of this goal will not only help us to understand the role of JNK in the assembly of podosome rosettes but also shed lights on the regulatory mechanisms of those structures. To achieve this goal, three specific aims are proposed:Aim 1. Establishment of the role of JNKs in podosome rosette formation. (1st year)Aim 2. Examination of the significance of the MKK-JNK-JIP complex in podosome rosette formation. (2nd year)Aim 3. Identification of the downstream effectors for JNKs to regulate podosome rosettes. (3rd year)
其他識別: NSC100-2320-B005-004-MY3
Appears in Collections:生命科學系所

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