hCASK调控p21～（WAF1/CIP1）表达机制的研究
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摘要
烧(创)伤不仅导致机体局部发生一系列病变,同时还可引发不同程度的全身性反应,许多细胞及细胞因子参与,涉及细胞运动、粘附、通讯、增殖和分化等细胞生物学的各个方面。烧伤、创伤后修复是一个错综复杂而有序的过程,损伤后修复的整个过程与细胞信号转导和增殖调控密切相关,而细胞增殖和分化的调控依赖于细胞周期的精密调节,研究细胞增殖和分化的机制对于伤后创面愈合以及预防瘢痕形成具有重要的意义。
本室研究发现,人钙/钙调蛋白依赖丝氨酸蛋白激酶(hCASK)可以抑制ECV304细胞增殖,而其抑制细胞增殖的作用机制尚不清楚。对此深入探讨将有助于我们正确理解烧(创)伤后机体组织修复、皮肤再生以及瘢痕增生的病理生理现象和发生机理。
hCASK是一种主要表达于上皮细胞和神经原的多结构域蛋白分子,主要功能是做为支架蛋白质(scaffolds),利用其多蛋白结构域,结合功能相关的蛋白分子,形成的多蛋白复合物,参与构建细胞膜骨架、维持细胞连接,细胞黏附,调节靶蛋白亚细胞定位,参与细胞内外信号转导和基因表达调控等许多重要的细胞生理过程。我们研究发现,人ECV304细胞中hCASK与分化抑制因子1(Id1)存在特异性的相互作用,Id1很可能是CASK的一个下游信号。Id1是bHLH家族的负调控因子,在促进细胞增殖、抑制细胞分化的过程中起重要作用。本室研究发现,强制表达CASK的ECV304细胞增殖缓慢,并且能不同程度地诱导细胞周期相关蛋白p21、p16等表达上调,而外源性siRNA下调CASK表达后,能促进ECV304细胞增殖,而且证实CASK参与细胞增殖调控可能与Id1的功能有关,但其机制尚不清楚。文献报道,某些哺乳动物细胞中,Id1通过负调节bHLH转录因子,抑制p21WAF1/CIP1、p16INK4a基因表达,促进细胞增殖。因此,我们推测,细胞周期抑制因子p21WAF1/CIP1、p16INK4a等很可能是CASK-Id1信号通路的重要效应分子。本项课题研究中,我们在筛选细胞周期相关蛋白的基础上,围绕p21这个关键分子,对CASK-Id1信号通路做了一些相关研究。
我们首先采用RNA干扰技术(RNAi),应用质粒载体介导的细胞内小干扰RNA(siRNA)表达策略,设计和构建了针对CASK、Id1的siRNA表达质粒,分别转染ECV304细胞,筛选并建立缺陷表达的细胞株,结合前期已经构建的CASK诱导表达
Background
Burns and trauma can not only lead to a series of pathological changes in the body, but also cause different degrees of systemic responses, including cellular adherence, signal transduction, proliferation and differentiation.Wound repair after burns and trauma is a complicated process, which have close relationship with the regulation of cell proliferation and cellular signal transduction. The cell proliferation and differentiation depends on the regulation of cell cycle. So, the research on the cell proliferation and differentiation is vital for the prevention of scar formation and wound healing.
hCASK (human calcium/calmodulin-dependent serine protein kinase)is a member of the membrane associated guanylate kinase (MAGUK) family, which is consist of a group of conserved cytoskeletal proteins. CASK, as a scaffolding protein, participates in intracellular signaling pathways. CASK may play an important role in cytoskeleton assembly, signal transduction, cell junction formation, cell proliferation, et al.
Our previous studies have shown that ECV304 cell proliferation was restrained, and the expression of p21WAF1/CIP1 and p16INK4a were up-regulated by the induction of hCASK.However, the mechanism is not clear.
Recently, we have confirmed that hCASK bound to Id1 through its GUK domain, and Id1 might be involved in the cell growth mediated by CASK. CASK seemed to be an upstream signal of Id-bHLH pathway that regulated cell cycle and proliferation of ECV304 cells.
Id1 family of helix-loop-helix(HLH) proteins does not possess a basic DNA binding domain and functions as a dominant-negative regulator of basic DNA proteins through the formation of inactive heterodimers with intact bHLH transcription factors. Id family has been implicated in regulating a variety of cellular processes, including cellular growth, differentiation, apoptosis, senescence, neoplastic transformation, but it is not well elucidated on the upstream signal of Id protein.
本室研究发现,人钙/钙调蛋白依赖丝氨酸蛋白激酶(hCASK)可以抑制ECV304细胞增殖,而其抑制细胞增殖的作用机制尚不清楚。对此深入探讨将有助于我们正确理解烧(创)伤后机体组织修复、皮肤再生以及瘢痕增生的病理生理现象和发生机理。
hCASK是一种主要表达于上皮细胞和神经原的多结构域蛋白分子,主要功能是做为支架蛋白质(scaffolds),利用其多蛋白结构域,结合功能相关的蛋白分子,形成的多蛋白复合物,参与构建细胞膜骨架、维持细胞连接,细胞黏附,调节靶蛋白亚细胞定位,参与细胞内外信号转导和基因表达调控等许多重要的细胞生理过程。我们研究发现,人ECV304细胞中hCASK与分化抑制因子1(Id1)存在特异性的相互作用,Id1很可能是CASK的一个下游信号。Id1是bHLH家族的负调控因子,在促进细胞增殖、抑制细胞分化的过程中起重要作用。本室研究发现,强制表达CASK的ECV304细胞增殖缓慢,并且能不同程度地诱导细胞周期相关蛋白p21、p16等表达上调,而外源性siRNA下调CASK表达后,能促进ECV304细胞增殖,而且证实CASK参与细胞增殖调控可能与Id1的功能有关,但其机制尚不清楚。文献报道,某些哺乳动物细胞中,Id1通过负调节bHLH转录因子,抑制p21WAF1/CIP1、p16INK4a基因表达,促进细胞增殖。因此,我们推测,细胞周期抑制因子p21WAF1/CIP1、p16INK4a等很可能是CASK-Id1信号通路的重要效应分子。本项课题研究中,我们在筛选细胞周期相关蛋白的基础上,围绕p21这个关键分子,对CASK-Id1信号通路做了一些相关研究。
我们首先采用RNA干扰技术(RNAi),应用质粒载体介导的细胞内小干扰RNA(siRNA)表达策略,设计和构建了针对CASK、Id1的siRNA表达质粒,分别转染ECV304细胞,筛选并建立缺陷表达的细胞株,结合前期已经构建的CASK诱导表达
Background
Burns and trauma can not only lead to a series of pathological changes in the body, but also cause different degrees of systemic responses, including cellular adherence, signal transduction, proliferation and differentiation.Wound repair after burns and trauma is a complicated process, which have close relationship with the regulation of cell proliferation and cellular signal transduction. The cell proliferation and differentiation depends on the regulation of cell cycle. So, the research on the cell proliferation and differentiation is vital for the prevention of scar formation and wound healing.
hCASK (human calcium/calmodulin-dependent serine protein kinase)is a member of the membrane associated guanylate kinase (MAGUK) family, which is consist of a group of conserved cytoskeletal proteins. CASK, as a scaffolding protein, participates in intracellular signaling pathways. CASK may play an important role in cytoskeleton assembly, signal transduction, cell junction formation, cell proliferation, et al.
Our previous studies have shown that ECV304 cell proliferation was restrained, and the expression of p21WAF1/CIP1 and p16INK4a were up-regulated by the induction of hCASK.However, the mechanism is not clear.
Recently, we have confirmed that hCASK bound to Id1 through its GUK domain, and Id1 might be involved in the cell growth mediated by CASK. CASK seemed to be an upstream signal of Id-bHLH pathway that regulated cell cycle and proliferation of ECV304 cells.
Id1 family of helix-loop-helix(HLH) proteins does not possess a basic DNA binding domain and functions as a dominant-negative regulator of basic DNA proteins through the formation of inactive heterodimers with intact bHLH transcription factors. Id family has been implicated in regulating a variety of cellular processes, including cellular growth, differentiation, apoptosis, senescence, neoplastic transformation, but it is not well elucidated on the upstream signal of Id protein.
引文
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