Role of apoptosis for regenerative proliferation

描述（由申请人提供）：凋亡诱导增殖（AiP）描述了最近发现的凋亡细胞具有诱导邻近存活细胞增殖的能力，从而补偿其损失。例如，尽管电离辐射会导致高达60%的大量凋亡组织损失，果蝇的翅膀成像盘却能诱导再生细胞增殖，从而产生正常比例和大小的成年翅膀。出乎意料的是，在包括果蝇、非洲爪蟾、九头蛇、小鼠和人类癌症在内的几种生物中获得的证据表明，包括肿瘤在内的截肢或其他损伤组织的再生AiP依赖于非凋亡功能的凋亡半胱天蛋白酶（高度特异性的细胞死亡蛋白酶）。虽然在过去几年中取得了进展，但仍然很差

DESCRIPTION (provided by applicant): Apoptosis-induced proliferation (AiP) describes the recently made discovery that apoptotic cells have the ability to induce proliferation of neighboring surviving cells, thus compensating for their loss. For instance, despite massive apoptotic tissue loss of up to 60% triggered by ionizing radiation, Drosophila wing imaginal discs induce regenerative cell proliferation which generates adult wings of normal proportion and size. Unexpectedly, evidence obtained in several organisms including Drosophila, Xenopus, Hydra, Mouse and human cancer suggests that regenerative AiP of amputated or otherwise damaged tissues including tumors depends on apoptotic caspases (highly specific cell death proteases) in a non-apoptotic function. Although progress has been made in the last few years, it is still poorly understood how caspases promote this non- apoptotic role in regenerative proliferation. The overall objective of this project is to identify the genes and elucidate the mechanisms of AiP using Drosophila as a model of gene discovery. Our approach is to induce apoptosis upstream, but simultaneously block apoptosis downstream of its AiP-promoting activity. Under these conditions, cells are kept alive ('undead'), but can still promote AiP because the block of apoptosis is downstream of its AiP-promoting activity. Because 'undead' cells do not die, but continue to promote AiP, they produce significant overgrowth phenotypes which provide convenient assays for genetic screening. These screening assays followed by phenotypic characterization of the identified genes will be explored in this project to address the objective. This project is also very relevant for understanding of human cancer. There are many similarities between tumor cells and 'undead' cells. Tumor cells are often apoptosis-incompetent due to inactivation of apoptotic genes or upregulation of anti-apoptotic genes. If this block of apoptosis occurs downstream of a potentially AiP-inducing activity of 'undead' tumor cells, this activity may significantly contribute to tumor growth which has indeed recently been shown. Furthermore, radio- and chemotherapy attempt to cure cancer by killing tumor cells. However, relapse of treated tumors is frequently observed and may be due to AiP-promoting activity of 'undead' tumor cells. In summary, this project promises to improve our understanding of both regenerative proliferation under normal conditions and tumor phenotypes under pathological conditions.