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

细胞凋亡是组织正常发育和稳态的一个基本机制，它负责清除不需要的和潜在危险的细胞。凋亡在半胱天酶的激活中达到高潮，半胱天酶是一类半胱氨酸蛋白酶，在几乎所有细胞中都以失活酶原的形式表达。在caspase家族中，caspase-3 （casp-3）在细胞凋亡中发挥重要作用，并负责切割一系列重要蛋白来实现细胞死亡程序。由于不适当的半胱天冬酶激活可能会产生可怕的后果，因此它的激活受到严格控制。多年来，casp-3的激活一直被认为是诱导细胞凋亡的同义词。然而，新兴的研究结果现在挑战了casp-3作为细胞死亡的义务执行者的简单观点。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干细胞的增殖。casp-3的促凋亡活性在这种细胞群中转向增殖的确切机制迄今尚未被研究。本提案的总体目标是破译casp-3的致命潜力如何重新聚焦以实现细胞增殖，并获得体内差异细胞死亡依赖和独立的casp-3信号传导模式的全面机械见解。我们假设细胞的内在因素（如翻译后修饰）和外在因素（如不同干细胞壁龛内的信号传导）都有助于casp-3激活的最终结果。该项目不仅将提供对这些功能的生理意义的见解，而且最终也有助于理解不平衡的casp-3信号传导如何促进癌症的发展。或者，将信号平衡从细胞死亡转移到细胞增殖可能是驱动组织再生的理想策略。

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.