RESUMO
Caspases are well known for their role as executioners of apoptosis. However, recent studies have revealed that these lethal enzymes also have important mitogenic functions. Caspases can promote proliferation through autonomous regulation of the cell cycle, as well as by induction of secreted signals, which have a profound impact in neighboring tissues. Here, I review the proliferative role of caspases during development and homeostasis, in addition to their key regenerative function during tissue repair upon injury. Furthermore, the emerging properties of apoptotic caspases as drivers of carcinogenesis are discussed, as well as their involvement in other diseases. Finally, I examine further effects of caspases regulating death and survival in a non-autonomous manner.
Assuntos
Caspases/metabolismo , Animais , Apoptose , Proliferação de Células , HumanosRESUMO
Apoptosis, in contrast to other forms of cell death such as necrosis, was originally regarded as a 'silent' mechanism of cell elimination designed to degrade the contents of doomed cells. However, during the past decade it has become clear that apoptotic cells can produce diverse signals that have a profound impact on neighboring cells and tissues. For example, apoptotic cells can release factors that influence the proliferation and survival of adjacent tissues. Apoptosis can also affect tissue movement and morphogenesis by modifying tissue tension in surrounding cells. As we review here, these findings reveal unexpected roles for apoptosis in tissue remodeling during development, as well as in regeneration and cancer.
Assuntos
Apoptose/fisiologia , Crescimento e Desenvolvimento/fisiologia , Morfogênese/fisiologia , Neoplasias/fisiopatologia , Regeneração/fisiologia , Transdução de Sinais/fisiologia , Animais , Autofagia/fisiologia , Humanos , Necrose/fisiopatologiaRESUMO
Senescence is a form of cellular aging that limits the proliferative capacity of cells. Senescence can be triggered by different stress stimuli, such as DNA damage or oncogene activation. Two recent articles published in Cell have uncovered an unexpected role for cellular senescence during development, as a process that contributes to remodeling and patterning of the embryo. These findings are exciting and have important implications for the understanding of normal developmental and the evolutionary origin of senescence.
Assuntos
Senescência Celular , Desenvolvimento Embrionário , Saco Endolinfático/embriologia , Mesonefro/embriologia , Animais , Feminino , Humanos , MasculinoRESUMO
Apoptotic cells can produce signals to instruct cells in their local environment, including ones that stimulate engulfment and proliferation. We identified a novel mode of communication by which apoptotic cells induce additional apoptosis in the same tissue. Strong induction of apoptosis in one compartment of the Drosophila wing disc causes apoptosis of cells in the other compartment, indicating that dying cells can release long-range death factors. We identified Eiger, the Drosophila tumor necrosis factor (TNF) homolog, as the signal responsible for apoptosis-induced apoptosis (AiA). Eiger is produced in apoptotic cells and, through activation of the c-Jun N-terminal kinase (JNK) pathway, is able to propagate the initial apoptotic stimulus. We also show that during coordinated cell death of hair follicle cells in mice, TNF-α is expressed in apoptotic cells and is required for normal cell death. AiA provides a mechanism to explain cohort behavior of dying cells that is seen both in normal development and under pathological conditions. DOI:http://dx.doi.org/10.7554/eLife.01004.001.
Assuntos
Apoptose/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Drosophila , Folículo Piloso/citologia , MAP Quinase Quinase 4/metabolismo , Camundongos , Transdução de Sinais , Asas de Animais/citologiaRESUMO
Mutant larvae for the Drosophila gene lethal giant larva (lgl) develop neoplastic tumors in imaginal discs. However, lgl mutant clones do not form tumors when surrounded by wild-type tissue, suggesting the existence of a tumor-suppressing mechanism. We have investigated the tumorigenic potential of lgl mutant cells by generating wing compartments that are entirely mutant for lgl and also inducing clones of various genetic combinations of lgl(-) cells. We find that lgl(-) compartments can grow indefinitely but lgl(-) clones are eliminated by cell competition. lgl mutant cells may form tumors if they acquire constitutive activity of the Ras pathway (lgl(-) UAS-ras(V12)), which confers proliferation advantage through inhibition of the Hippo pathway. Yet, the majority of lgl(-) UAS-ras(V12) clones are eliminated in spite of their high proliferation rate. The formation of a tumor requires in addition the formation of a microenvironment that allows mutant cells to evade cell competition.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Comunicação Celular , Proliferação de Células , Proteínas de Drosophila/genética , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Larva/citologia , Larva/genética , Larva/metabolismo , Microscopia Confocal , Mutação , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Proteínas Supressoras de Tumor/genética , Asas de Animais/citologia , Asas de Animais/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
Non-lethal stress treatments (X-radiation or heat shock) administered to Drosophila imaginal discs induce massive apoptosis, which may eliminate more that 50% of the cells. Yet the discs are able to recover to form final structures of normal size and pattern. Thus, the surviving cells have to undergo additional proliferation to compensate for the cell loss. The finding that apoptotic cells ectopically express dpp and wg suggested that ectopic Dpp/Wg signalling might be responsible for compensatory proliferation. We have tested this hypothesis by analysing the response to irradiation-induced apoptosis of disc compartments that are mutant for dpp, for wg, or for both. We find that there is compensatory proliferation in these compartments, indicating that the ectopic Dpp/Wg signalling generated by apoptotic cells is not involved. However, we demonstrate that this ectopic Dpp/Wg signalling is responsible for the hyperplastic overgrowths that appear when apoptotic ('undead') cells are kept alive with the caspase inhibitor P35. We also show that the ectopic Dpp/Wg signalling and the overgrowths caused by undead cells are due to a non-apoptotic function of the JNK pathway. We propose that the compensatory growth is simply a homeostatic response of wing compartments, which resume growth after massive cellular loss until they reach the final correct size. The ectopic Dpp/Wg signalling associated with apoptosis is inconsequential in compartments with normal apoptotic cells, which die soon after the stress event. In compartments containing undead cells, the adventitious Dpp/Wg signalling results in hyperplastic overgrowths.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/citologia , Drosophila/metabolismo , Proteína Wnt1/metabolismo , Animais , Animais Geneticamente Modificados , Apoptose/efeitos da radiação , Proliferação de Células , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Proteínas de Drosophila/genética , Genes de Insetos , Homeostase , Hiperplasia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Modelos Biológicos , Mutação , Transdução de Sinais , Asas de Animais/citologia , Asas de Animais/crescimento & desenvolvimento , Asas de Animais/metabolismo , Proteína Wnt1/genéticaRESUMO
Apoptosis (programmed cell death) is a conserved process in all animals, used to eliminate damaged or unwanted cells after stress events or during normal development to sculpt larval or adult structures. In Drosophila, it is known that stress events such as irradiation or heat shock give rise to high apoptotic levels which remove more than 50% of cells in imaginal discs. However, the surviving cells are able to restore normal size and pattern, indicating that they undergo additional proliferation. This compensatory proliferation is still poorly understood. One widely used method to study the properties of apoptotic cells is to keep them alive by expressing in them the baculoviral protein P35, which blocks the activity of the effector caspases. These "undead" cells acquire special features, such as the emission of the growth signals Dpp and Wg, changes in cellular morphology and induction of proliferation in neighbouring cells. Here, we review the various methods used in Drosophila to block apoptosis and its consequences, and focus on the generation and properties of undead cells in the wing imaginal disc. We describe their effects in epithelial architecture and growth in some detail, and discuss the possible relationship between undead cells and compensatory proliferation.
Assuntos
Apoptose/fisiologia , Proliferação de Células , Drosophila melanogaster/fisiologia , Animais , Apoptose/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Modelos Biológicos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/fisiologia , Proteína Wnt1/genética , Proteína Wnt1/fisiologiaRESUMO
In Drosophila, stresses such as x-irradiation or severe heat shock can cause most epidermal cells to die by apoptosis. Yet, the remaining cells recover from such assaults and form normal adult structures, indicating that they undergo extra growth to replace the lost cells. Recent studies of cells in which the cell death pathway is blocked by expression of the caspase inhibitor P35 have raised the possibility that dying cells normally regulate this compensatory growth by serving as transient sources of mitogenic signals. Caspase-inhibited cells that initiate apoptosis do not die. Instead, they persist in an "undead" state in which they ectopically express the signaling genes decapentaplegic (dpp) and wingless (wg) and induce abnormal growth and proliferation of surrounding tissue. Here, using mutations to abolish Dpp and/or Wg signaling by such undead cells, we show that Dpp and Wg constitute opposing stimulatory and inhibitory signals that regulate this excess growth and proliferation. Strikingly, we also found that, when Wg signaling is blocked, unfettered Dpp signaling by undead cells transforms their neighbors into neoplastic tumors, provided that caspase activity is also blocked in the responding cells. This phenomenon may provide a paradigm for the formation of neoplastic tumors in mammalian tissues that are defective in executing the cell death pathway. Specifically, we suggest that stress events (exposure to chemical mutagens, viral infection, or irradiation) that initiate apoptosis in such tissues generate undead cells, and that imbalances in growth regulatory signals sent by these cells can induce the oncogenic transformation of neighboring cells.
Assuntos
Apoptose , Caspases/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Neoplasias/metabolismo , Transdução de Sinais , Animais , Apoptose/efeitos da radiação , Inibidores de Caspase , Transformação Celular Neoplásica , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Suscetibilidade a Doenças , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Neoplasias/genética , Neoplasias/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima/genética , Proteína Wnt1 , Raios XRESUMO
Programmed cell death or apoptosis plays an important role in the development of multicellular organisms and can also be induced by various stress events. In the Drosophila wing imaginal disc there is little apoptosis in normal development but X-rays can induce high apoptotic levels, which eliminate a large fraction of the disc cells. Nevertheless, irradiated discs form adult patterns of normal size, indicating the existence of compensatory mechanisms. We have characterised the apoptotic response of the wing disc to X-rays and heat shock and also the developmental consequences of compromising apoptosis. We have used the caspase inhibitor P35 to prevent the death of apoptotic cells and found that it causes increased non-autonomous cell proliferation, invasion of compartments and persistent misexpression of the wingless (wg) and decapentaplegic (dpp) signalling genes. We propose that a feature of cells undergoing apoptosis is to activate wg and dpp, probably as part of the mechanism to compensate for cell loss. If apoptotic cells are not eliminated, they continuously emit Wg and Dpp signals, which results in developmental aberrations. We suggest that a similar process of uncoupling apoptosis initiation and cell death may occur during tumour formation in mammalian cells.