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

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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.