Shifting the balance: Mechanistic control of cell death dependent and independent functions of caspase-3 in epidermal stem cells.

改变平衡：表皮干细胞中 caspase-3 细胞死亡依赖性和独立功能的机械控制。

• 批准号: 445151255
• 负责人: Dr. Nathalie Tisch
• 金额: --
• 依托单位: Technion - Israel Institute of Technology
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/445151255?language=en
• 关键词: Shifting; balance; Mechanistic; control; cell

A fundamental mechanism for proper tissue development and homeostasis is apoptosis, which is responsible for the elimination of undesired and potentially dangerous cell. Apoptosis culminates in the activation of caspases, which are a class of cysteine proteases that are expressed as inactive zymogens in almost all cells. Of the caspase family, caspase-3 (casp-3) plays an instrumental role in apoptosis and is responsible for cleaving a range of important proteins to implement the cell death program. Since improper caspase activation may yield dire consequences, its activation is tightly controlled. For many years, activation of casp-3 has been rather synonymous with the induction of apoptosis. However, emerging findings now challenge the simplistic view of casp-3 as an obligated executioner of cellular demise. In the skin, casp-3 regulates apoptosis in hair follicle stem cells, however, recent work has shown that it actually induces proliferation in stem cells found in the sebaceous gland adjacent to the hair follicle. The precise mechanisms by which the pro-apoptotic activity of casp-3 is switched towards proliferation in this cell population has so far not been investigated.The overall goal of this proposal is to decipher how the lethal potential of casp-3 can be refocused to achieve cellular proliferation and to gain comprehensive mechanistical insight into the differential cell death dependent and independent casp-3 signaling modalities in vivo. We hypothesize that both cell intrinsic (e.g. posttranslational modifications) and extrinsic factors (e.g. signaling within different stem cell niches) contribute to the ultimate outcome of casp-3 activation. This project will not only provide insights into the physiological implications of these functions, but ultimately also help to understand how disbalanced casp-3 signaling might contribute to cancer development. Alternatively, shifting the signaling balance from cell death to proliferation could be an ideal strategy for driving tissue regeneration.

正常组织发育和体内平衡的基本机制是细胞凋亡，其负责消除不需要的和潜在危险的细胞。凋亡在半胱天冬酶的激活中达到高潮，半胱天冬酶是一类半胱氨酸蛋白酶，在几乎所有细胞中表达为无活性的酶原。在caspase家族中，caspase-3（casp-3）在细胞凋亡中起着重要的作用，负责切割一系列重要的蛋白质以实现细胞死亡程序。由于不适当的半胱天冬酶激活可能产生可怕的后果，其激活受到严格控制。多年来，casp-3的激活一直与细胞凋亡的诱导同义。然而，新的发现现在挑战casp-3作为细胞死亡的义务刽子手的简单观点。在皮肤中，casp-3调节毛囊干细胞的凋亡，然而，最近的研究表明，它实际上诱导毛囊附近皮脂腺中的干细胞增殖。迄今为止，尚未研究casp-3的促凋亡活性在该细胞群中转向增殖的精确机制。该提案的总体目标是破译casp-3的致死潜力如何重新聚焦以实现细胞增殖，并获得全面的机制深入了解体内细胞死亡依赖性和独立性casp-3信号传导模式。我们假设细胞内在因素（如翻译后修饰）和外在因素（如不同干细胞小生境内的信号传导）都对casp-3激活的最终结果有贡献。这个项目不仅将提供这些功能的生理意义的见解，但最终也有助于了解如何失衡casp-3信号可能有助于癌症的发展。或者，将信号平衡从细胞死亡转移到增殖可能是驱动组织再生的理想策略。